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Vona R, Cittadini C, Ortona E, Matarrese P. Sex Disparity in Cancer: Role of Autophagy and Estrogen Receptors. Cells 2025; 14:273. [PMID: 39996745 PMCID: PMC11854201 DOI: 10.3390/cells14040273] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Revised: 01/24/2025] [Accepted: 02/07/2025] [Indexed: 02/26/2025] Open
Abstract
Autophagy, a cellular process essential for maintaining homeostasis, plays a fundamental role in recycling damaged components and in adapting to stress. The dysregulation of autophagy is implicated in numerous human diseases, including cancer, where it exhibits a dual role as both a suppressor and a promoter, depending on the context and the stage of tumor development. The significant sex differences observed in autophagic processes are determined by biological factors, such as genetic makeup and sex hormones. Estrogens, through their interaction with specific receptors, modulate autophagy and influence tumor progression, therapy resistance, and the immune response to tumors. In females, the escape from X inactivation and estrogen signaling may be responsible for the advantages, in terms of lower incidence and longer survival, observed in oncology. Women often show better responses to traditional chemotherapy, while men respond better to immunotherapy. The action of sex hormones on the immune system could contribute to these differences. However, women experience more severe adverse reactions to anticancer drugs. The estrogen/autophagy crosstalk-involved in multiple aspects of the tumor, i.e., development, progression and the response to therapy-deserves an in-depth study, as it could highlight sex-specific mechanisms useful for designing innovative and gender-tailored treatments from the perspective of precision medicine.
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Affiliation(s)
- Rosa Vona
- Center for Gender-Specific Medicine, National Institute of Health, 00161 Rome, Italy; (C.C.); (E.O.)
| | | | | | - Paola Matarrese
- Center for Gender-Specific Medicine, National Institute of Health, 00161 Rome, Italy; (C.C.); (E.O.)
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Wang L, Kong Q, Leng X, Leung H, Li Y. The sphingosine-1-phosphate signaling pathway (sphingosine-1-phosphate and its receptor, sphingosine kinase) and epilepsy. Epilepsia Open 2025; 10:55-73. [PMID: 39727628 PMCID: PMC11803289 DOI: 10.1002/epi4.13112] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2024] [Revised: 11/08/2024] [Accepted: 11/20/2024] [Indexed: 12/28/2024] Open
Abstract
Epilepsy is one of the common chronic neurological diseases, affecting more than 70 million people worldwide. The brains of people with epilepsy exhibit a pathological and persistent propensity for recurrent seizures. Epilepsy often coexists with cardiovascular disease, cognitive dysfunction, depression, etc., which seriously affects the patient's quality of life. Although our understanding of epilepsy has advanced, the pathophysiological mechanisms leading to epileptogenesis, drug resistance, and associated comorbidities remain largely unknown. The use of newer antiepileptic drugs has increased, but this has not improved overall outcomes. We need to deeply study the pathogenesis of epilepsy and find drugs that can not only prevent the epileptogenesis and interfere with the process of epileptogenesis but also treat epilepsy comorbidities. Sphingosine-1-phosphate (S1P) is an important lipid molecule. It not only forms the basis of cell membranes but is also an important bioactive mediator. It can not only act as a second messenger in cells to activate downstream signaling pathways but can also exert biological effects by being secreted outside cells and binding to S1P receptors on the cell membrane. Fingolimod (FTY720) is the first S1P receptor modulator developed and approved for the treatment of multiple sclerosis. More and more studies have proven that the S1P signaling pathway is closely related to epilepsy, drug-resistant epilepsy, epilepsy comorbidities, or other epilepsy-causing diseases. However, there is much controversy over the role of certain natural molecules in the pathway and receptor modulators (such as FTY720) in epilepsy. Here, we summarize and analyze the role of the S1P signaling pathway in epilepsy, provide a basis for finding potential therapeutic targets and/or epileptogenic biomarkers, analyze the reasons for these controversies, and put forward our opinions. PLAIN LANGUAGE SUMMARY: This article combines the latest research literature at home and abroad to review the sphingosine 1-phosphate signaling pathway and epileptogenesis, drug-resistant epilepsy, epilepsy comorbidities, other diseases that can cause epilepsy, as well as the sphingosine-1-phosphate signaling pathway regulators and epilepsy, with the expectation of providing a certain theoretical basis for finding potential epilepsy treatment targets and/or epileptogenic biomarkers in the sphingosine-1-phosphate signaling pathway.
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Affiliation(s)
- Lin Wang
- Department of NeurologyAffiliated Hospital of Jining Medical UniversityJining CityChina
- Epilepsy CenterAffiliated Hospital of Jining Medical UniversityJining CityChina
- The Chinese University of Hong Kong, Department of Medicine and TherapeuticsThe Chinese University of Hong Kong, Central AveHong KongHong Kong
| | - Qingxia Kong
- Department of NeurologyAffiliated Hospital of Jining Medical UniversityJining CityChina
- Epilepsy CenterAffiliated Hospital of Jining Medical UniversityJining CityChina
| | - Xinyi Leng
- The Chinese University of Hong Kong, Department of Medicine and TherapeuticsThe Chinese University of Hong Kong, Central AveHong KongHong Kong
| | - Howan Leung
- Division of Neurology, Department of Medicine and Therapeutics, Prince of Wales Hospital7/F Clinical Science Building, Prince of Wales HospitalHong KongHong Kong
| | - Yang Li
- Department of OncologyAffiliated Hospital of Jining Medical UniversityJining CityChina
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Zhang X, Zhang H, Wang J, Chen Y, Lin J, Wang Q, Wu C, Chen H, Lin Y. Curcumin attenuates ulcerative colitis via regulation of Sphingosine kinases 1/NF-κB signaling pathway. Biofactors 2025; 51:e70001. [PMID: 39832759 DOI: 10.1002/biof.70001] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 01/10/2025] [Indexed: 01/22/2025]
Abstract
Curcumin, a compound from Curcuma longa L., has significant anti-inflammatory properties. However, the mechanisms underlying its anti-inflammatory activity in dextran sodium sulfate (DSS)-induced ulcerative colitis (UC) remain inadequately understood. This study aimed to further elucidate the molecular mechanisms of curcumin DSS-induced UC mice. Our data showed that curcumin alleviated DSS-induced colitis by reducing intestinal damage and inflammation, increasing goblet cells in colon tissues. Enzyme-linked immunosorbent assay revealed that curcumin reduced the expression of inflammatory cytokines (tumor necrosis factor-alpha, interleukin-1β, and interleukin-8) in serum and myeloperoxidase in colon tissues. A comprehensive analysis integrating network pharmacology and RNA sequencing (RNA-seq) revealed significant enrichment of the nuclear factor kappa B (NF-κB) signaling pathways. Notably, RNA-seq analysis demonstrated that curcumin significantly downregulated the mRNA expression of sphingosine kinase 1 (SphK1). Furthermore, molecular docking analysis showed that curcumin can bind to SphK1 and NF-κB. Additionally, curcumin was found to inhibit the activation of the SphK1/NF-κB signaling pathway in DSS-induced UC colon tissue. This study addresses pharmacologic and mechanistic perspectives of curcumin that ameliorates DSS-induced UC and inflammatory response.
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Affiliation(s)
- Xiuli Zhang
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
| | - Hao Zhang
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
| | - Jingting Wang
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
| | - Yangyi Chen
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
| | - Jiumao Lin
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
| | - Qingshui Wang
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
| | - Cheng Wu
- Basic Medical Experimental Teaching Center, School of Basic Medical Sciences, Fujian Medical University, Fuzhou, Fujian, China
| | - Hui Chen
- Department of Gastroenterology, The First Affiliated Hospital of Fujian Medical University, Fuzhou, Fujian, China
| | - Yao Lin
- College of Integrative Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian, China
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Liu H, Li X, Liu W, Zhang C, Zhang S, Zhou X, Bode AM, Luo X. DHRS2-induced SPHK1 downregulation contributes to the cell growth inhibition by Trichothecin in colorectal carcinoma. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119846. [PMID: 39284549 DOI: 10.1016/j.bbamcr.2024.119846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/03/2024] [Revised: 09/02/2024] [Accepted: 09/08/2024] [Indexed: 09/22/2024]
Abstract
BACKGROUND Deregulation of lipid metabolism is one of the most prominent metabolic features in cancer. The activation of sphingolipid metabolic pathways affects the proliferation, invasion, angiogenesis, chemoresistance, and immune escape of tumors, including colorectal cancer (CRC). Dehydrogenase/reductase member 2 (DHRS2), which belongs to the short-chain dehydrogenase/reductase (SDR) family, has been reported to participate in the regulation of lipid metabolism and impact on cancer progression. Trichothecin (TCN) is a sesquiterpenoid metabolite originating from an endophytic fungus of the herbal plant Maytenus hookeri Loes. Studies have shown that TCN exerts a broad-spectrum antitumor activity. METHODS We evaluated the proliferative ability of CRC cells by CCK8 and colony formation assays. A metabolite profiling using liquid chromatography coupled with mass spectrometry (LC/MS) was adopted to identify the proximal metabolite changes linked to DHRS2 overexpression. RNA stability assay and RNA immunoprecipitation (RIP) experiments were applied to determine the post-transcriptional regulation of SPHK1 expression by DHRS2. We used flow cytometry to detect changes in cell cycle and cell apoptosis of CRC cells in the absence or presence of TCN. RESULTS We demonstrate that DHRS2 hampers the sphingosine kinases 1 (SPHK1)/sphingosine 1-phosphate (S1P) metabolic pathway to inhibit CRC cell growth. DHRS2 directly binds to SPHK1 mRNA to accelerate its degradation in a post-transcriptionally regulatory manner. Moreover, we illustrate that SPHK1 downregulation induced by DHRS2 contributes to TCN-induced growth inhibition of CRC. CONCLUSIONS The present study provides a mechanistic connection among metabolic enzymes, metabolites, and the malignant progression of CRC. Moreover, TCN could be developed as a potential pharmacological tool against CRC by the induction of DHRS2 and targeting SPHK1/S1P metabolic pathway.
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Affiliation(s)
- Huiwen Liu
- Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, PR China; NHC Key Laboratory of Carcinogenesis, the Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan 410078, PR China
| | - Xiang Li
- Department of Pathology, Xiangya Hospital, Central South University, Changsha, Hunan 410078, PR China
| | - Wenbin Liu
- Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, PR China; Department of Pathology, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, PR China
| | - Chunhong Zhang
- Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, PR China; NHC Key Laboratory of Carcinogenesis, the Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan 410078, PR China
| | - Shuzhao Zhang
- Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, PR China; NHC Key Laboratory of Carcinogenesis, the Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan 410078, PR China
| | - Xinran Zhou
- Hengyang Medical College, University of South China, Hengyang 421001 Hunan, PR China
| | - Ann M Bode
- The Hormel Institute, University of Minnesota, Austin, MN 55912, USA
| | - Xiangjian Luo
- Hunan Key Laboratory of Oncotarget Gene, Hunan Cancer Hospital and the Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 410013, PR China; NHC Key Laboratory of Carcinogenesis, the Key Laboratory of Carcinogenesis and Invasion, Chinese Ministry of Education, Cancer Research Institute, School of Basic Medicine, Central South University, Changsha, Hunan 410078, PR China; Key Laboratory of Biological Nanotechnology of National Health Commission, Central South University, Changsha, Hunan 410078, China.
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Liu B, Zhou J, Jiang B, Tang B, Liu T, Lei P. The role of ACER2 in intestinal sphingolipid metabolism and gastrointestinal cancers. Front Immunol 2024; 15:1511283. [PMID: 39650647 PMCID: PMC11621088 DOI: 10.3389/fimmu.2024.1511283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 11/04/2024] [Indexed: 12/11/2024] Open
Abstract
Sphingolipids, particularly sphingosine-1-phosphate (S1P), are bioactive lipids involved in regulating cellular processes such as proliferation, apoptosis, inflammation, and tumor progression. Alkaline ceramidase 2 (ACER2) plays a critical role in sphingolipid metabolism by catalyzing the hydrolysis of ceramide to sphingosine, which is subsequently converted to S1P. Dysregulation of ACER2 has been implicated in various gastrointestinal cancers, including colorectal cancer, gastric cancer, and hepatocellular carcinoma. ACER2-mediated sphingolipid signaling, particularly through the SphK/S1P pathway, influences cancer development by modulating immune responses, inflammation, and the balance between cell survival and death. This review examines the physiological functions of ACER2, and its role in sphingolipid metabolism, and its contribution to the pathogenesis of gastrointestinal cancers. Understanding the mechanisms by which ACER2 regulates tumor progression and immune modulation may open new avenues for targeted therapies in gastrointestinal malignancies.
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Affiliation(s)
- Binggang Liu
- Department of Gastrointestinal Surgery, the Central Hospital of Yongzhou, Yongzhou, China
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Sukocheva OA, Neganova ME, Aleksandrova Y, Burcher JT, Chugunova E, Fan R, Tse E, Sethi G, Bishayee A, Liu J. Signaling controversy and future therapeutical perspectives of targeting sphingolipid network in cancer immune editing and resistance to tumor necrosis factor-α immunotherapy. Cell Commun Signal 2024; 22:251. [PMID: 38698424 PMCID: PMC11064425 DOI: 10.1186/s12964-024-01626-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Accepted: 04/21/2024] [Indexed: 05/05/2024] Open
Abstract
Anticancer immune surveillance and immunotherapies trigger activation of cytotoxic cytokine signaling, including tumor necrosis factor-α (TNF-α) and TNF-related apoptosis-inducing ligand (TRAIL) pathways. The pro-inflammatory cytokine TNF-α may be secreted by stromal cells, tumor-associated macrophages, and by cancer cells, indicating a prominent role in the tumor microenvironment (TME). However, tumors manage to adapt, escape immune surveillance, and ultimately develop resistance to the cytotoxic effects of TNF-α. The mechanisms by which cancer cells evade host immunity is a central topic of current cancer research. Resistance to TNF-α is mediated by diverse molecular mechanisms, such as mutation or downregulation of TNF/TRAIL receptors, as well as activation of anti-apoptotic enzymes and transcription factors. TNF-α signaling is also mediated by sphingosine kinases (SphK1 and SphK2), which are responsible for synthesis of the growth-stimulating phospholipid, sphingosine-1-phosphate (S1P). Multiple studies have demonstrated the crucial role of S1P and its transmembrane receptors (S1PR) in both the regulation of inflammatory responses and progression of cancer. Considering that the SphK/S1P/S1PR axis mediates cancer resistance, this sphingolipid signaling pathway is of mechanistic significance when considering immunotherapy-resistant malignancies. However, the exact mechanism by which sphingolipids contribute to the evasion of immune surveillance and abrogation of TNF-α-induced apoptosis remains largely unclear. This study reviews mechanisms of TNF-α-resistance in cancer cells, with emphasis on the pro-survival and immunomodulatory effects of sphingolipids. Inhibition of SphK/S1P-linked pro-survival branch may facilitate reactivation of the pro-apoptotic TNF superfamily effects, although the role of SphK/S1P inhibitors in the regulation of the TME and lymphocyte trafficking should be thoroughly assessed in future studies.
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Affiliation(s)
- Olga A Sukocheva
- Department of Hepatology, Royal Adelaide Hospital, Adelaide, SA, 5000, Australia.
| | - Margarita E Neganova
- Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka, 142432, Russian Federation
- Arbuzov Institute of Organic and Physical Chemistry, Federal Research Center, Kazan Scientific Center, Russian Academy of Sciences, Kazan, 420088, Russian Federation
| | - Yulia Aleksandrova
- Institute of Physiologically Active Compounds at Federal Research Center of Problems of Chemical Physics and Medicinal Chemistry, Russian Academy of Sciences, Chernogolovka, 142432, Russian Federation
- Arbuzov Institute of Organic and Physical Chemistry, Federal Research Center, Kazan Scientific Center, Russian Academy of Sciences, Kazan, 420088, Russian Federation
| | - Jack T Burcher
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, 34211, USA
| | - Elena Chugunova
- Arbuzov Institute of Organic and Physical Chemistry, Federal Research Center, Kazan Scientific Center, Russian Academy of Sciences, Kazan, 420088, Russian Federation
| | - Ruitai Fan
- Department of Radiation Oncology, Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Edmund Tse
- Department of Hepatology, Royal Adelaide Hospital, Adelaide, SA, 5000, Australia
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore
| | - Anupam Bishayee
- College of Osteopathic Medicine, Lake Erie College of Osteopathic Medicine, Bradenton, FL, 34211, USA.
| | - Junqi Liu
- Department of Radiation Oncology, Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China.
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Alkafaas SS, Elsalahaty MI, Ismail DF, Radwan MA, Elkafas SS, Loutfy SA, Elshazli RM, Baazaoui N, Ahmed AE, Hafez W, Diab M, Sakran M, El-Saadony MT, El-Tarabily KA, Kamal HK, Hessien M. The emerging roles of sphingosine 1-phosphate and SphK1 in cancer resistance: a promising therapeutic target. Cancer Cell Int 2024; 24:89. [PMID: 38419070 PMCID: PMC10903003 DOI: 10.1186/s12935-024-03221-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Accepted: 01/09/2024] [Indexed: 03/02/2024] Open
Abstract
Cancer chemoresistance is a problematic dilemma that significantly restrains numerous cancer management protocols. It can promote cancer recurrence, spreading of cancer, and finally, mortality. Accordingly, enhancing the responsiveness of cancer cells towards chemotherapies could be a vital approach to overcoming cancer chemoresistance. Tumour cells express a high level of sphingosine kinase-1 (SphK1), which acts as a protooncogenic factor and is responsible for the synthesis of sphingosine-1 phosphate (S1P). S1P is released through a Human ATP-binding cassette (ABC) transporter to interact with other phosphosphingolipids components in the interstitial fluid in the tumor microenvironment (TME), provoking communication, progression, invasion, and tumor metastasis. Also, S1P is associated with several impacts, including anti-apoptotic behavior, metastasis, mesenchymal transition (EMT), angiogenesis, and chemotherapy resistance. Recent reports addressed high levels of S1P in several carcinomas, including ovarian, prostate, colorectal, breast, and HCC. Therefore, targeting the S1P/SphK signaling pathway is an emerging therapeutic approach to efficiently attenuate chemoresistance. In this review, we comprehensively discussed S1P functions, metabolism, transport, and signaling. Also, through a bioinformatic framework, we pointed out the alterations of SphK1 gene expression within different cancers with their impact on patient survival, and we demonstrated the protein-protein network of SphK1, elaborating its sparse roles. Furthermore, we made emphasis on different machineries of cancer resistance and the tight link with S1P. We evaluated all publicly available SphK1 inhibitors and their inhibition activity using molecular docking and how SphK1 inhibitors reduce the production of S1P and might reduce chemoresistance, an approach that might be vital in the course of cancer treatment and prognosis.
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Affiliation(s)
- Samar Sami Alkafaas
- Molecular Cell Biology Unit, Division of Biochemistry, Department of Chemistry, Faculty of Science, Tanta University, Tanta, 31527, Egypt.
| | - Mohamed I Elsalahaty
- Biochemistry Division, Department of Chemistry, Faculty of Science, Tanta University, Tanta, 31527, Egypt.
| | - Doha F Ismail
- Biochemistry Division, Department of Chemistry, Faculty of Science, Tanta University, Tanta, 31527, Egypt
| | - Mustafa Ali Radwan
- Biochemistry Division, Department of Chemistry, Faculty of Science, Tanta University, Tanta, 31527, Egypt
| | - Sara Samy Elkafas
- Production Engineering and Mechanical Design Department, Faculty of Engineering, Menofia University, Menofia, Egypt
- Faculty of Control System and Robotics, ITMO University, Saint-Petersburg, 197101, Russia
| | - Samah A Loutfy
- Virology and Immunology Unit, Cancer Biology Department, National Cancer Institute, Cairo University, Cairo, Egypt
- Nanotechnology Research Center, British University, Cairo, Egypt
| | - Rami M Elshazli
- Biochemistry and Molecular Genetics Unit, Department of Basic Sciences, Faculty of Physical Therapy, Horus University-Egypt, New Damietta, 34517, Egypt
| | - Narjes Baazaoui
- Biology Department, College of Sciences and Arts Muhayil Assir, King Khalid University, Abha 61421, Saudi Arabia
| | - Ahmed Ezzat Ahmed
- Biology Department, College of Science, King Khalid University, Abha 61413, Saudi Arabia
| | - Wael Hafez
- NMC Royal Hospital, 16th Street, 35233, Khalifa, Abu Dhabi, United Arab Emirates
- Medical Research Division, Department of Internal Medicine, The National Research Centre, Cairo 11511, Egypt
| | - Mohanad Diab
- Burjeel Hospital Abu Dhabi, Abu Dhabi, United Arab Emirates
| | - Mohamed Sakran
- Biochemistry Division, Department of Chemistry, Faculty of Science, Tanta University, Tanta, 31527, Egypt
- Biochemistry Department, Faculty of Science, University of Tabuk, Tabuk 47512, Saudi Arabia
| | - Mohamed T El-Saadony
- Department of Agricultural Microbiology, Faculty of Agriculture, Zagazig University, Zagazig 44511, Egypt
| | - Khaled A El-Tarabily
- Department of Biology, College of Science, United Arab Emirates University, Al-Ain 15551, United Arab Emirates
| | - Hani K Kamal
- Anatomy and Histology, Faculty of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
| | - Mohamed Hessien
- Molecular Cell Biology Unit, Division of Biochemistry, Department of Chemistry, Faculty of Science, Tanta University, Tanta, 31527, Egypt
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Wei J, Ge X, Qian Y, Jiang K, Chen X, Lu W, Yang H, Fu D, Fang Y, Zhou X, Xiao Q, Tang Y, Ding K. Development and verification of a combined immune- and cancer-associated fibroblast related prognostic signature for colon adenocarcinoma. Front Immunol 2024; 15:1291938. [PMID: 38312843 PMCID: PMC10834644 DOI: 10.3389/fimmu.2024.1291938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2023] [Accepted: 01/04/2024] [Indexed: 02/06/2024] Open
Abstract
INTRODUCTION To better understand the role of immune escape and cancer-associated fibroblasts (CAFs) in colon adenocarcinoma (COAD), an integrative analysis of the tumor microenvironment was performed using a set of 12 immune- and CAF-related genes (ICRGs). METHODS Univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analyses were used to establish a prognostic signature based on the expression of these 12 genes (S1PR5, AEN, IL20RB, FGF9, OSBPL1A, HSF4, PCAT6, FABP4, KIF15, ZNF792, CD1B and GLP2R). This signature was validated in both internal and external cohorts and was found to have a higher C-index than previous COAD signatures, confirming its robustness and reliability. To make use of this signature in clinical settings, a nomogram incorporating ICRG signatures and key clinical parameters, such as age and T stage, was developed. Finally, the role of S1PR5 in the immune response of COAD was validated through in vitro cytotoxicity experiments. RESULTS The developed nomogram exhibited slightly improved predictive accuracy compared to the ICRG signature alone, as indicated by the areas under the receiver operating characteristic curves (AUC, nomogram:0.838; ICRGs:0.807). The study also evaluated the relationships between risk scores (RS) based on the expression of the ICRGs and other key immunotherapy variables, including immune checkpoint expression, immunophenoscore (IPS), and microsatellite instability (MSI). Integration of these variables led to more precise prediction of treatment efficacy, enabling personalized immunotherapy for COAD patients. Knocking down S1PR5 can enhance the efficacy of PD-1 monoclonal antibody, promoting the cytotoxicity of T cells against HCT116 cells ((p<0.05). DISCUSSION These findings indicate that the ICRG signature may be a valuable tool for predicting prognostic risk, evaluating the efficacy of immunotherapy, and tailoring personalized treatment options for patients with COAD.
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Affiliation(s)
- Jingsun Wei
- Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Cancer Center of Zhejiang University, Hangzhou, Zhejiang, China
| | - Xiaoxu Ge
- Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Cancer Center of Zhejiang University, Hangzhou, Zhejiang, China
| | - Yucheng Qian
- Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Cancer Center of Zhejiang University, Hangzhou, Zhejiang, China
| | - Kai Jiang
- Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Cancer Center of Zhejiang University, Hangzhou, Zhejiang, China
| | - Xin Chen
- Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Cancer Center of Zhejiang University, Hangzhou, Zhejiang, China
| | - Wei Lu
- Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Cancer Center of Zhejiang University, Hangzhou, Zhejiang, China
| | - Hang Yang
- Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Cancer Center of Zhejiang University, Hangzhou, Zhejiang, China
| | - Dongliang Fu
- Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Cancer Center of Zhejiang University, Hangzhou, Zhejiang, China
| | - Yimin Fang
- Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Cancer Center of Zhejiang University, Hangzhou, Zhejiang, China
| | - Xinyi Zhou
- Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Cancer Center of Zhejiang University, Hangzhou, Zhejiang, China
| | - Qian Xiao
- Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Cancer Center of Zhejiang University, Hangzhou, Zhejiang, China
| | - Yang Tang
- Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Cancer Center of Zhejiang University, Hangzhou, Zhejiang, China
| | - Kefeng Ding
- Department of Colorectal Surgery and Oncology (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education, Key Laboratory of Molecular Biology in Medical Sciences), The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Cancer Center of Zhejiang University, Hangzhou, Zhejiang, China
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9
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González-Aretia D, Hernández-Coronado CG, Guzmán A, Medina-Moctezuma ZB, Gutiérrez CG, Rosales-Torres AM. Sphingosine-1-phosphate mediates FSH-induced cell viability but not steroidogenesis in bovine granulosa cells. Theriogenology 2024; 213:90-96. [PMID: 37820497 DOI: 10.1016/j.theriogenology.2023.10.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 10/02/2023] [Accepted: 10/05/2023] [Indexed: 10/13/2023]
Abstract
Follicle-stimulating hormone (FSH) stimulates the proliferation, survival, and estradiol synthesis of granulosa cells by binding to their G protein-coupled receptors. Although FSH activates sphingosine kinase-1 (SPHK1) to induce sphingosine-1-phosphate (S1P) synthesis, which is required to mediate the proliferative and survival effect of this gonadotrophin, the mechanisms, and the role of S1P in estradiol synthesis have not been reported. This study aimed to evaluate the importance of FSH-induced S1P synthesis as a mediator of the effects of this gonadotrophin on granulosa cell viability and steroidogenesis and to determine if FSH-induced S1P synthesis depends on estradiol, cAMP, PKA, or PKC. To achieve these objectives, we tested the effects of FSH, a sphingosine kinase-1 inhibitor (SKI-178), estradiol and inhibitors of aromatase, cAMP, PKA, and PKC (Formestane, MDL-12330A, H-89 dihydrochloride hydrate and Calphostin C respectively), on granulosa cell viability, S1P and estradiol production, and the mRNA expression of CYP19A1 and STAR in four in vitro culture experiments. The addition of FSH (1 ng/mL) increased (P < 0.05) granulosa cells number and S1P concentration in the culture media. Conversely, the addition of SKI-178 (10 μM) reduced (P < 0.05) S1P concentration negating the effect of FSH on cell viability. Inhibition of PKC and PKA, but not cAMP, reduced (P < 0.05) S1P secretion of FSH treated granulosa cells. It is important to note that the reduction in S1P secretion was strong (49 %) with the use of the PKC inhibitor. The use of formestane (10 μg) did not modify (P > 0.05) S1P secretion in FSH-treated cells; however, the addition of 5 or 10 ng/mL of estradiol increased (P < 0.05) S1P secretion. Finally, FSH increased (P < 0.05) estradiol concentration in the culture media, but this effect was not blocked by the inhibition of S1P synthesis. Similarly, FSH, SKI-178 or their combination did not modify the mRNA expression of CYP19A1 and STAR. In conclusion, S1P synthesis is stimulated FSH in granulosa cells and mediated mainly by PKC. S1P in turn promotes the granulosa cell viability, however, this does not influence estradiol synthesis. Additionally, estradiol synthesis induced by FSH is not essential for S1P synthesis, however high estradiol concentration may stimulate S1P production by granulosa cells.
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Affiliation(s)
- David González-Aretia
- Doctorado en Ciencias Biológicas y de la Salud, Universidad Autónoma Metropolitana, Ciudad de México, Mexico
| | | | - Adrián Guzmán
- Departamento Producción Agrícola y Animal, Universidad Autónoma Metropolitana unidad Xochimilco, Ciudad de México, Mexico
| | | | - Carlos G Gutiérrez
- Departamento de Reproducción, Facultad de Medicina Veterinaria y Zootecnia, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | - Ana María Rosales-Torres
- Departamento Producción Agrícola y Animal, Universidad Autónoma Metropolitana unidad Xochimilco, Ciudad de México, Mexico.
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10
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Fugio LB, Silva G, Ferraz CL, Trevisan GL, Coeli-Lacchini FB, Garcia CB, Sousa LO, Malta TM, Gil CD, Leopoldino AM. Accumulation of sphingosine kinase 2 protein induces malignant transformation in oral keratinocytes associated with stemness, autophagy, senescence, and proliferation. BIOCHIMICA ET BIOPHYSICA ACTA. MOLECULAR CELL RESEARCH 2024; 1871:119616. [PMID: 37898377 DOI: 10.1016/j.bbamcr.2023.119616] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2023] [Revised: 10/18/2023] [Accepted: 10/19/2023] [Indexed: 10/30/2023]
Abstract
Sphingosine-1-phosphate (S1P) signaling has been widely explored as a therapeutic target in cancer. Sphingosine kinase 2 (SK2), one of the kinases that phosphorylate sphingosine, has a cell type and cell location-dependent mechanism of action, so the ability of SK2 to induce cell cycle arrest, apoptosis, proliferation, and survival is strongly influenced by the cell-context. In contrast to SK1, which is widely studied in different types of cancer, including head and neck cancer, the role of SK2 in the development and progression of oral cancer is still poorly understood. In order to elucidate SK2 role in oral cancer, we performed the overexpression of SK2 in non-tumor oral keratinocyte cell (NOK SK2) and in oral squamous cell carcinoma (HN12 SK2), and RNA interference for SK2 in another oral squamous cell carcinoma (HN13 shSK2). In our study we demonstrate for the first time that accumulation of SK2 can be a starting point for oncogenesis and transforms a non-tumor oral keratinocyte (NOK-SI) into highly aggressive tumor cells, even acting on cell plasticity. Furthermore, in oral metastatic cell line (HN12), SK2 contributed even more to the tumorigenesis, inducing proliferation and tumor growth. Our work reveals the intriguing role of SK2 as an oral tumor promoter and regulator of different pathways and cellular processes.
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Affiliation(s)
- Lais Brigliadori Fugio
- Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil
| | - Gabriel Silva
- Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil
| | - Camila Lopes Ferraz
- Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil
| | - Glauce Lunardelli Trevisan
- Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil
| | - Fernanda Borchers Coeli-Lacchini
- Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil
| | - Cristiana Bernadelli Garcia
- Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil
| | - Lucas Oliveira Sousa
- Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil
| | - Tathiane Maistro Malta
- Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil
| | - Cristiane Damas Gil
- Department of Cell Biology, Federal University of the State of São Paulo, Brazil
| | - Andréia Machado Leopoldino
- Department of Clinical Analysis, Toxicology and Food Sciences, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Brazil.
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11
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Shakeel I, Khan S, Roy S, Sherwani F, Ahmad SF, Sohal SS, Afzal M, Hassan MI. Investigating potential of cholic acid, syringic acid, and mangiferin as cancer therapeutics through sphingosine kinase 1 inhibition. Int J Biol Macromol 2023; 253:127036. [PMID: 37788733 DOI: 10.1016/j.ijbiomac.2023.127036] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 09/01/2023] [Accepted: 09/21/2023] [Indexed: 10/05/2023]
Abstract
The signaling of sphingosine kinase 1 (SphK1) and sphingosine-1-phosphate (S1P) regulates various diseases, including multiple sclerosis, atherosclerosis, rheumatoid arthritis, inflammation-related ailments, diabetes, and cancer. SphK1 is considered an attractive potential drug target and is extensively explored in cancer and other inflammatory diseases. In this study, we have investigated the inhibitory potential and binding affinity of SphK1 with cholic acid (CA), syringic acid (SA), and mangiferin (MF) using a combination of docking and molecular dynamics (MD) simulation studies followed by experimental measurements of binding affinity and enzyme inhibition assays. We observed these compounds bind to SphK1 with a significantly high affinity and eventually inhibit its kinase activity with IC50 values of 28.23 μM, 33.35 μM, and 57.2 μM for CA, SA, and MF, respectively. Further, the docking and 100 ns MD simulation studies showed that CA, SA, and MF bind with the active site residues of SphK1 with favorable energy and strong non-covalent interactions that might be accountable for inhibiting its kinase activity. Our finding indicates that CA, SA, and MF may be implicated in designing novel anti-cancer therapeutics with an improved affinity and lesser side effects by targeting SphK1.
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Affiliation(s)
- Ilma Shakeel
- Department of Zoology, Aligarh Muslim University, Aligarh, India; Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Shama Khan
- South African Medical Research Council, Vaccines and Infectious Diseases Analytics Research Unit, Faculty of Health Science, School of Pathology, University of the Witwatersrand, Johannesburg, South Africa
| | - Sonam Roy
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Fakhir Sherwani
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India
| | - Sheikh F Ahmad
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Sukhwinder Singh Sohal
- Respiratory Translational Research Group, Department of Laboratory Medicine, School of Health Sciences, College of Health and Medicine, University of Tasmania, Launceston 7001, Tasmania, Australia
| | - Mohammad Afzal
- Department of Zoology, Aligarh Muslim University, Aligarh, India.
| | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi 110025, India.
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12
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Xu X, Han Y, Zhu T, Fan F, Wang X, Liu Y, Luo D. The role of SphK/S1P/S1PR signaling pathway in bone metabolism. Biomed Pharmacother 2023; 169:115838. [PMID: 37944444 DOI: 10.1016/j.biopha.2023.115838] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Revised: 10/27/2023] [Accepted: 11/01/2023] [Indexed: 11/12/2023] Open
Abstract
There are a large number of people worldwide who suffer from osteoporosis, which imposes a huge economic burden, so it is necessary to explore the underlying mechanisms to achieve better supportive and curative care outcomes. Sphingosine kinase (SphK) is an enzyme that plays a crucial role in the synthesis of sphingosine-1-phosphate (S1P). S1P with paracrine and autocrine activities that act through its cell surface S1P receptors (S1PRs) and intracellular signals. In osteoporosis, S1P is indispensable for both normal and disease conditions. S1P has complicated roles in regulating osteoblast and osteoclast, respectively, and there have been exciting developments in understanding how SphK/S1P/S1PR signaling regulates these processes in response to osteoporosis therapy. Here, we review the proliferation, differentiation, apoptosis, and functions of S1P, specifically detailing the roles of S1P and S1PRs in osteoblasts and osteoclasts. Finally, we focus on the S1P-based therapeutic approaches in bone metabolism, which may provide valuable insights into potential therapeutic strategies for osteoporosis.
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Affiliation(s)
- Xuefeng Xu
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China; Institute of Chinese Medicine, Guangdong Pharmaceutical University, China
| | - Yi Han
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China; Institute of Chinese Medicine, Guangdong Pharmaceutical University, China
| | - Tianxin Zhu
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China; Institute of Chinese Medicine, Guangdong Pharmaceutical University, China
| | - Faxin Fan
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China; Institute of Chinese Medicine, Guangdong Pharmaceutical University, China
| | - Xin Wang
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China; Institute of Chinese Medicine, Guangdong Pharmaceutical University, China
| | - Yuqing Liu
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China; Institute of Chinese Medicine, Guangdong Pharmaceutical University, China
| | - Duosheng Luo
- Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, China; Guangdong Metabolic Diseases Research Center of Integrated Chinese and Western Medicine, China; Guangdong TCM Key Laboratory for Metabolic Diseases, Guangzhou 510006, China; Institute of Chinese Medicine, Guangdong Pharmaceutical University, China.
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13
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Wang W, Zhao Y, Zhu G. The role of sphingosine-1-phosphate in the development and progression of Parkinson's disease. Front Cell Neurosci 2023; 17:1288437. [PMID: 38179204 PMCID: PMC10764561 DOI: 10.3389/fncel.2023.1288437] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Accepted: 11/27/2023] [Indexed: 01/06/2024] Open
Abstract
Parkinson's disease (PD) could be viewed as a proteinopathy caused by changes in lipids, whereby modifications in lipid metabolism may lead to protein alterations, such as the accumulation of alpha-synuclein (α-syn), ultimately resulting in neurodegeneration. Although the loss of dopaminergic neurons in the substantia nigra is the major clinical manifestation of PD, the etiology of it is largely unknown. Increasing evidence has highlighted the important role of lipids in the pathophysiology of PD. Sphingosine-1-phosphate (S1P), a signaling lipid, has been suggested to have a potential association with the advancement and worsening of PD. Therefore, better understanding the mechanisms and regulatory proteins is of high interest. Most interestingly, S1P appears to be an important target to offers a new strategy for the diagnosis and treatment of PD. In this review, we first introduce the basic situation of S1P structure, function and regulation, with a special focus on the several pathways. We then briefly describe the regulation of S1P signaling pathway on cells and make a special focused on the cell growth, proliferation and apoptosis, etc. Finally, we discuss the function of S1P as potential therapeutic target to improve the clinical symptoms of PD, and even prevent the progression of the PD. In the context of PD, the functions of S1P modulators have been extensively elucidated. In conclusion, S1P modulators represent a novel and promising therapeutic principle and therapeutic method for PD. However, more research is required before these drugs can be considered as a standard treatment option for PD.
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Affiliation(s)
- Wang Wang
- Department of Neurology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
- School of Medicine & Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Yang Zhao
- Department of Neurology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
| | - Guoxue Zhu
- Department of Neurology, Nanjing Hospital of Chinese Medicine Affiliated to Nanjing University of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, China
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14
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Wagner JM, Wille A, Fueth M, Weske S, Lotzien S, Reinkemeier F, Wallner C, Sogorski A, Dittfeld S, Becerikli M, Schildhauer TA, Lehnhardt M, Levkau B, Behr B. Pharmacological elevation of sphingosine-1-phosphate by S1P lyase inhibition accelerates bone regeneration after post-traumatic osteomyelitis. J Cell Mol Med 2023; 27:3786-3795. [PMID: 37710406 PMCID: PMC10718149 DOI: 10.1111/jcmm.17952] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 08/15/2023] [Accepted: 09/01/2023] [Indexed: 09/16/2023] Open
Abstract
Posttraumatic osteomyelitis and the ensuing bone defects are a debilitating complication after open fractures with little therapeutic options. We have recently identified potent osteoanabolic effects of sphingosine-1-phosphate (S1P) signalling and have now tested whether it may beneficially affect bone regeneration after infection. We employed pharmacological S1P lyase inhibition by 4-deoxypyrodoxin (DOP) to raise S1P levels in vivo in an unicortical long bone defect model of posttraumatic osteomyelitis in mice. In a translational approach, human bone specimens of clinical osteomyelitis patients were treated in organ culture in vitro with DOP. Bone regeneration was assessed by μCT, histomorphometry, immunohistology and gene expression analysis. The role of S1P receptors was addressed using S1PR3 deficient mice. Here, we present data that DOP treatment markedly enhanced osteogenesis in posttraumatic osteomyelitis. This was accompanied by greatly improved osteoblastogenesis and enhanced angiogenesis in the callus accompanied by osteoclast-mediated bone remodelling. We also identified the target of increased S1P to be the S1PR3 as S1PR3-/- mice showed no improvement of bone regeneration by DOP. In the human bone explants, bone mass significantly increased along with enhanced osteoblastogenesis and angiogenesis. Our data suggest that enhancement of S1P/S1PR3 signalling may be a promising therapeutic target for bone regeneration in posttraumatic osteomyelitis.
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Affiliation(s)
- Johannes M. Wagner
- Department of Plastic SurgeryBG University Hospital Bergmannsheil BochumBochumGermany
- Department of Trauma Surgery and General SurgeryBG University Hospital Bergmannsheil BochumBochumGermany
| | - Annalena Wille
- Institute of Molecular Medicine IIIUniversity Hospital Düsseldorf and Heinrich Heine Universität DüsseldorfDüsseldorfGermany
| | - Maria Fueth
- Department of Plastic SurgeryBG University Hospital Bergmannsheil BochumBochumGermany
| | - Sarah Weske
- Institute of Molecular Medicine IIIUniversity Hospital Düsseldorf and Heinrich Heine Universität DüsseldorfDüsseldorfGermany
| | - Sebastian Lotzien
- Department of Trauma Surgery and General SurgeryBG University Hospital Bergmannsheil BochumBochumGermany
| | - Felix Reinkemeier
- Department of Plastic SurgeryBG University Hospital Bergmannsheil BochumBochumGermany
| | - Christoph Wallner
- Department of Plastic SurgeryBG University Hospital Bergmannsheil BochumBochumGermany
| | - Alexander Sogorski
- Department of Plastic SurgeryBG University Hospital Bergmannsheil BochumBochumGermany
| | - Stephanie Dittfeld
- Department of Plastic SurgeryBG University Hospital Bergmannsheil BochumBochumGermany
| | - Mustafa Becerikli
- Department of Plastic SurgeryBG University Hospital Bergmannsheil BochumBochumGermany
| | - Thomas A. Schildhauer
- Department of Trauma Surgery and General SurgeryBG University Hospital Bergmannsheil BochumBochumGermany
| | - Marcus Lehnhardt
- Department of Plastic SurgeryBG University Hospital Bergmannsheil BochumBochumGermany
| | - Bodo Levkau
- Institute of Molecular Medicine IIIUniversity Hospital Düsseldorf and Heinrich Heine Universität DüsseldorfDüsseldorfGermany
| | - Björn Behr
- Department of Plastic SurgeryBG University Hospital Bergmannsheil BochumBochumGermany
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15
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Wu X, Wabitsch M, Yang J, Sakharkar MK. Effects of adipocyte-conditioned cell culture media on S1P treatment of human triple-negative breast cancer cells. PLoS One 2023; 18:e0286111. [PMID: 37220155 DOI: 10.1371/journal.pone.0286111] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Accepted: 05/09/2023] [Indexed: 05/25/2023] Open
Abstract
Sphingosine-1-phosphate (S1P) is a potent sphingolipid metabolite that regulates a wide range of biological functions such as cell proliferation, cell apoptosis and angiogenesis. Its cellular level is elevated in breast cancer, which, in turn, would promote cancer cell proliferation, survival, growth and metastasis. However, the cellular concentration of S1P is normally in the low nanomolar range, and our previous studies showed that S1P selectively induced apoptosis of breast cancer cells at high concentrations (high nanomolar to low micromolar). Thus, local administration of high-concentration S1P alone or in combination of chemotherapy agents could be used to treat breast cancer. The breast mainly consists of mammary gland and connective tissue stroma (adipose), which are dynamically interacting each other. Thus, in the current study, we evaluated how normal adipocyte-conditioned cell culture media (AD-CM) and cancer-associated adipocyte-conditioned cell culture media (CAA-CM) would affect high-concentration S1P treatment of triple-negative breast cancer (TNBC) cells. Both AD-CM and CAA-CM may suppress the anti-proliferative effect and reduce nuclear alteration/apoptosis caused by high-concentration S1P. This implicates that adipose tissue is likely to be detrimental to local high-concentration S1P treatment of TNBC. Because the interstitial concentration of S1P is about 10 times higher than its cellular level, we undertook a secretome analysis to understand how S1P would affect the secreted protein profile of differentiated SGBS adipocytes. At 100 nM S1P treatment, we identified 36 upregulated and 21 downregulated secretome genes. Most of these genes are involved in multiple biological processes. Further studies are warranted to identify the most important secretome targets of S1P in adipocytes and illustrate the mechanism on how these target proteins affect S1P treatment of TNBC.
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Affiliation(s)
- Xiyuan Wu
- College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada
| | - Martin Wabitsch
- Department of Pediatrics and Adolescent Medicine, Ulm University Medical Center, Ulm, Germany
| | - Jian Yang
- College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, SK, Canada
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16
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Chen H, Haddadi N, Zhu X, Hatoum D, Chen S, Nassif NT, Lin Y, McGowan EM. Expression Profile of Sphingosine Kinase 1 Isoforms in Human Cancer Tissues and Cells: Importance and Clinical Relevance of the Neglected 1b-Isoform. JOURNAL OF ONCOLOGY 2022; 2022:2250407. [PMID: 36532885 PMCID: PMC9750787 DOI: 10.1155/2022/2250407] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2022] [Revised: 11/12/2022] [Accepted: 11/17/2022] [Indexed: 09/28/2023]
Abstract
Background Overexpression of sphingosine kinase 1 (SphK1) is casually associated with many types of cancer, and inhibitors of SphK1 sensitize tumors to chemotherapy. SphK1 is expressed as two major isoforms, SphK1a and SphK1b. To date, no information has been reported on the SphK1 isoform expression profile and its clinical relevance. Objective The objective is to examine the expression profile of the SphK1a and SPhK1b isoforms in human cancer and noncancer tissues and cell lines and explore their clinical relevance. Methods We used PCR to qualitatively examine the expression profile of these two isoforms in breast, liver, and prostate cancer tissues plus paired adjacent tissues and in 11 cancer and normal cell lines (breast, cervical, bone, prostate, colon, brain, mesothelioma tumor and benign, and human kidney cells). Results We found that SphK1a was ubiquitously expressed in all cancer cells and tissues tested; in contrast, SphK1b was only expressed in selective cell types in breast, prostate, and lung cancer. Conclusions Our data suggest that SphK1a is important for generic SphK1/S1P functions, and SphK1b mediates specialized and/or unique pathways in a specific type of tissue and could be a biomarker for cancer. This discovery is important for future SphK1-related cancer research and may have clinical implications in drug development associated with SphK1-directed cancer treatment.
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Affiliation(s)
- Hongjie Chen
- Department of Traditional Chinese Medicine, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Nahal Haddadi
- School of Life Sciences, University of Technology Sydney, Broadway, NSW, Australia
| | - Xiaofeng Zhu
- Department of Transplant Surgery, First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
| | - Diana Hatoum
- School of Life Sciences, University of Technology Sydney, Broadway, NSW, Australia
- Public Health and College of Arts and Sciences, Phoenicia University, Daoudiye, Lebanon
| | - Size Chen
- Central Laboratory, First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Provincial Engineering Research Center for Esophageal Cancer Precision Therapy, Guangdong Pharmaceutical University, Guangzhou, China
| | - Najah T. Nassif
- School of Life Sciences, University of Technology Sydney, Broadway, NSW, Australia
| | - Yiguang Lin
- Department of Traditional Chinese Medicine, Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, China
- School of Life Sciences, University of Technology Sydney, Broadway, NSW, Australia
- Central Laboratory, First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
| | - Eileen M. McGowan
- School of Life Sciences, University of Technology Sydney, Broadway, NSW, Australia
- Central Laboratory, First Affiliated Hospital of Guangdong Pharmaceutical University, Guangzhou, China
- Guangdong Provincial Engineering Research Center for Esophageal Cancer Precision Therapy, Guangdong Pharmaceutical University, Guangzhou, China
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17
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Jia L, Zhu S, Zhu M, Huang L, Xu S, Luo Y, Xiao J, Su H, Huang S, Tan Q. Triptolide Inhibits the Biological Processes of HUVECs and HepG2 Cells via the Serine Palmitoyltransferase Long Chain Base Subunit 2/Sphingosine-1-Phosphate Signaling Pathway. DISEASE MARKERS 2022; 2022:9119423. [PMID: 36438896 PMCID: PMC9699786 DOI: 10.1155/2022/9119423] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/18/2022] [Revised: 08/12/2022] [Accepted: 10/11/2022] [Indexed: 09/10/2024]
Abstract
Triptolide (TP) has demonstrated innumerous biological effects and pharmacological potential against different cancer types. Hepatocellular carcinoma has a high incidence in men, and its incidence is increasing year by year. Studies have shown that angiogenesis plays an important role in the formation of tumors and that angiogenesis is closely related to tumor growth and metastasis. Deregulation of sphingolipids signaling has been associated with several pathological conditions, including cancer. In the present study, we aimed at exploring the potential molecular mechanism of TP's antivascular and antitumor effects in vitro from the perspective of sphinolipids. Human umbilical vein endothelial cells (HUVECs) and HepG2 cells were, respectively, treated with different concentrations of TP and transfected. Then, the effect of HUVECs on HepG2 cells was investigated using a three-dimensional coculture model system. CCK-8 assay was performed for cell proliferation. Cell migration and invasion abilities were assessed using the transwell assay. Cell adhesion and tube formation were detected by Matrigel. RT-PCR and western blotting were used to detect the mRNA and protein expression. The S1P production was measured via ELISA assay. Our results showed that TP inhibited HUVECs and HepG2 cells proliferation, migration, invasion, adhesion, angiogenesis, and serine palmitoyltransferase long chain base subunit 2 (SPTLC2) expression; upregulating SPTLC2 facilitated the proliferation, migration, invasion, adhesion, angiogenesis, and sphingosine-1-phosphate (S1P) production of HUVECs and HepG2 cells, while interfering with SPTLC2 expression inhibited them; HUVECs facilitated the proliferation, migration, invasion, S1P production, S1PR1, and S1PR2 expression of HepG2 cells, while S1PR3 expression was decreased. In conclusion, SPTLC2 may be associated with the antivascular and antitumor effects of TP, and SPTLC2 is expected to become a new marker for tumor therapy. HUVECs can promote the proliferation, migration, and invasion of HepG2 cells, which may be related to the S1P/sphingosine-1-phosphate receptor (S1PR) signaling pathway.
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Affiliation(s)
- Lulu Jia
- Clinical Pharmacy & Pharmacology Research Institute, Affiliated Hospital of Guilin Medical University, Guilin 541001, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin 541001, China
- China-USA Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, China
| | - Shengnan Zhu
- Clinical Pharmacy & Pharmacology Research Institute, Affiliated Hospital of Guilin Medical University, Guilin 541001, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin 541001, China
- China-USA Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, China
| | - Mingfei Zhu
- Clinical Pharmacy & Pharmacology Research Institute, Affiliated Hospital of Guilin Medical University, Guilin 541001, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin 541001, China
- China-USA Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, China
| | - Lingyue Huang
- Clinical Pharmacy & Pharmacology Research Institute, Affiliated Hospital of Guilin Medical University, Guilin 541001, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin 541001, China
- China-USA Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, China
| | - Siyuan Xu
- Clinical Pharmacy & Pharmacology Research Institute, Affiliated Hospital of Guilin Medical University, Guilin 541001, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin 541001, China
- China-USA Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, China
| | - Yuqin Luo
- Clinical Pharmacy & Pharmacology Research Institute, Affiliated Hospital of Guilin Medical University, Guilin 541001, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin 541001, China
- China-USA Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, China
| | - Juan Xiao
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin 541001, China
- China-USA Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, China
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Affiliated Hospital of Guilin Medical University, Guilin 541001, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, Affiliated Hospital of Guilin Medical University, Guilin 541001, China
| | - Huazhen Su
- Clinical Pharmacy & Pharmacology Research Institute, Affiliated Hospital of Guilin Medical University, Guilin 541001, China
| | - Shaoyuan Huang
- Clinical Pharmacy & Pharmacology Research Institute, Affiliated Hospital of Guilin Medical University, Guilin 541001, China
| | - Qinyou Tan
- Clinical Pharmacy & Pharmacology Research Institute, Affiliated Hospital of Guilin Medical University, Guilin 541001, China
- Laboratory of Hepatobiliary and Pancreatic Surgery, Affiliated Hospital of Guilin Medical University, Guilin 541001, China
- China-USA Lipids in Health and Disease Research Center, Guilin Medical University, Guilin 541001, China
- Guangxi Key Laboratory of Molecular Medicine in Liver Injury and Repair, Affiliated Hospital of Guilin Medical University, Guilin 541001, China
- Guangxi Health Commission Key Laboratory of Basic Research in Sphingolipid Metabolism Related Diseases, Affiliated Hospital of Guilin Medical University, Guilin 541001, China
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Hengst JA, Nduwumwami AJ, Raup-Konsavage WM, Vrana KE, Yun JK. Inhibition of Sphingosine Kinase Activity Enhances Immunogenic Cell Surface Exposure of Calreticulin Induced by the Synthetic Cannabinoid 5-epi-CP-55,940. Cannabis Cannabinoid Res 2022; 7:637-647. [PMID: 34846947 PMCID: PMC9587795 DOI: 10.1089/can.2021.0100] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Background: Endogenous and synthetic cannabinoids have been shown to induce cancer cell death through the accumulation of the sphingolipid, ceramide (Cer). Recently, we have demonstrated that Cer accumulation enhances the induction of immunogenic cell death (ICD). Objectives: The primary objective of this study was to demonstrate that (±) 5-epi CP 55,940 (5-epi), a by-product of the chemical synthesis of the synthetic cannabinoid CP 55,940, induces ICD in colorectal cancer (CRC) cells, and that modulation of the sphingolipid metabolic pathway through inhibition of the sphingosine kinases (SphKs) enhances these effects. Methods: A cell culture model system of human CRC cell lines was employed to measure the cell surface and intracellular production of markers of ICD. The effects of 5-epi, alone and in combination with SphK inhibitors, on production of Cer through the de novo sphingolipid synthesis pathway were measured by Liquid Chromatography - Tandem Mass Spectrometry (LC/MS/MS)-based sphingolipidomic analysis. Cell surface exposure of calreticulin (ectoCRT), a hallmark of ICD, was measured by flow cytometry. Examination of the effects of 5-epi, alone and in combination with SphK inhibitors, on the intracellular signaling pathway associated with ICD was conducted by immunoblot analysis of human CRC cell lines. Results: Sphingolipidomic analysis indicated that 5-epi induces the de novo sphingolipid synthetic pathway. 5-epi dose dependently induces cell surface exposure of ectoCRT, and inhibition of Cer metabolism through inhibition of the SphKs significantly enhances 5-epi-induced ectoCRT exposure in multiple CRC cell lines. 5-epi induces and SphK inhibition enhances activation of the cell death signaling pathway associated with ICD. Conclusions: This study is the first demonstration that cannabinoids can induce the cell surface expression of ectoCRT, and potentially induce ICD. Moreover, this study reinforces our previous observation of a role for Cer accumulation in the induction of ICD and extends this observation to the cannabinoids, agents not typically associated with ICD. Inhibition of SphKs enhanced the 5-epi-induced signaling pathways leading to ICD and production of ectoCRT. Overexpression of SphK1 has previously been associated with chemotherapy resistance. Thus, targeting the SphKs has the potential to reverse chemotherapy resistance and simultaneously enhance the antitumor immune response through enhancement of ICD induction.
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Affiliation(s)
- Jeremy A. Hengst
- Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - Asvelt J. Nduwumwami
- Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - Wesley M. Raup-Konsavage
- Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - Kent E. Vrana
- Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
| | - Jong K. Yun
- Department of Pharmacology, Pennsylvania State University College of Medicine, Hershey, Pennsylvania, USA
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19
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Uranbileg B, Kurano M, Kano K, Sakai E, Arita J, Hasegawa K, Nishikawa T, Ishihara S, Yamashita H, Seto Y, Ikeda H, Aoki J, Yatomi Y. Sphingosine 1-phosphate lyase facilitates cancer progression through converting sphingolipids to glycerophospholipids. Clin Transl Med 2022; 12:e1056. [PMID: 36125914 PMCID: PMC9488530 DOI: 10.1002/ctm2.1056] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 08/23/2022] [Accepted: 08/29/2022] [Indexed: 11/07/2022] Open
Abstract
BACKGROUND In addition to potent agonist properties for sphingosine 1-phosphate (S1P) receptors, intracellularly, S1P is an intermediate in metabolic conversion pathway from sphingolipids to glycerolysophospholipids (glyceroLPLs). We hypothesized that this S1P metabolism and its products might possess some novel roles in the pathogenesis of cancer, where S1P lyase (SPL) is a key enzyme. METHODS The mRNA levels of sphingolipid-related and other cancer-related factors were measured in human hepatocellular carcinoma (HCC), colorectal cancer, and esophageal cancer patients' tumours and in their adjacent non-tumour tissues. Phospholipids (PL) and glyceroLPLs were measured by using liquid chromatography-tandem mass spectrometry (LC-MS/MS). In-vitro experiments were performed in Colon 26 cell line with modulation of the SPL and GPR55 expressions. Xenograft model was used for determination of the cancer progression and for pharmacological influence. RESULTS Besides high SPL levels in human HCC and colon cancer, SPL levels were specifically and positively linked with levels of glyceroLPLs, including lysophosphatidylinositol (LPI). Overexpression of SPL in Colon 26 cells resulted in elevated levels of LPI and lysophosphatidylglycerol (LPG), which are agonists of GPR55. SPL overexpression-enhanced cell proliferation was inhibited by GPR55 silencing. Conversely, inhibition of SPL led to the opposite outcome and reversed by adding LPI, LPG, and metabolites generated during S1P degradation, which is regulated by SPL. The xenograft model results suggested the contribution of SPL and glyceroLPLs to tumour progression depending on levels of SPL and GPR55. Moreover, the pharmacological inhibition of SPL prevented the progression of cancer. The underlying mechanisms for the SPL-mediated cancer progression are the activation of p38 and mitochondrial function through the LPI, LPG-GPR55 axis and the suppression of autophagy in a GPR55-independent manner. CONCLUSION A new metabolic pathway has been proposed here in HCC and colon cancer, SPL converts S1P to glyceroLPLs, mainly to LPI and LPG, and facilitates cancer development.
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Affiliation(s)
- Baasanjav Uranbileg
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Makoto Kurano
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Kuniyuki Kano
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Eri Sakai
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Junichi Arita
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Kiyoshi Hasegawa
- Hepato-Biliary-Pancreatic Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Takeshi Nishikawa
- Surgical Oncology and Vascular Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Soichiro Ishihara
- Surgical Oncology and Vascular Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Hiroharu Yamashita
- Gastrointestinal Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan.,Division of Digestive Surgery, Department of Surgery, Nihon University School of Medicine, Tokyo, Japan
| | - Yasuyuki Seto
- Gastrointestinal Surgery Division, Department of Surgery, The University of Tokyo, Tokyo, Japan
| | - Hitoshi Ikeda
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Junken Aoki
- Department of Health Chemistry, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo, Japan
| | - Yutaka Yatomi
- Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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20
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Deng S, Ao Z, Liu B, She Q, Du J, Liu Y, Jing X. Correlation between plasma sphingosine-1-phosphate and the occurrence and severity of coronary heart disease in postmenopausal women. Menopause 2022; 29:920-925. [PMID: 35881936 DOI: 10.1097/gme.0000000000002004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
OBJECTIVE Sphingosine-1-phosphate (S1P) is a bioactive sphingosine with antiatherosclerotic effects. The incidence of coronary heart disease (CHD) increases significantly among women after menopause. We explored the relationship between plasma S1P levels and the occurrence and severity of CHD in postmenopausal women. METHODS Postmenopausal women admitted to our hospital for coronary angiography because of chest pain-like symptoms were included in our study. By 1:1 age matching (age difference ≤5 y), 166 women in the CHD group and control group were enrolled. The plasma S1P concentration was determined, and the Gensini score was calculated to decide the severity of CHD. RESULTS Plasma S1P levels were significantly lower in the CHD group of postmenopausal women ( P < 0.001). S1P (odds ratio, 0.952; 95% CI, 0.934-0.970) was an independent predictor of the occurrence of CHD in postmenopausal women. The area under the curve for S1P to predict the occurrence of CHD was 0.653 (95% CI, 0.595-0.712), and the cutoff value was 96.89 ng/mL. The plasma S1P level was the lowest in the high-tertile group of the Gensini score ( P < 0.001), and the plasma S1P (odds ratio, 0.948; 95% CI, 0.926-0.970) was an independent predictor of a high Gensini score in postmenopausal women with CHD. CONCLUSIONS Plasma S1P is an independent risk factor of the occurrence and severity of CHD in postmenopausal women. The occurrence and aggravation of CHD in postmenopausal women may be related to levels of S1P.
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Affiliation(s)
- Songbai Deng
- From the Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zehui Ao
- the Department of Cardiology, People's Hospital of Xiushan Country, Chongqing, China
| | - Bin Liu
- From the Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Qiang She
- From the Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Jianlin Du
- From the Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yajie Liu
- From the Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Xiaodong Jing
- From the Department of Cardiology, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
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21
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Wollny T, Wnorowska U, Piktel E, Suprewicz Ł, Król G, Głuszek K, Góźdź S, Kopczyński J, Bucki R. Sphingosine-1-Phosphate-Triggered Expression of Cathelicidin LL-37 Promotes the Growth of Human Bladder Cancer Cells. Int J Mol Sci 2022; 23:7443. [PMID: 35806446 PMCID: PMC9267432 DOI: 10.3390/ijms23137443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 06/30/2022] [Accepted: 07/01/2022] [Indexed: 02/04/2023] Open
Abstract
It has been proven that tumour growth and progression are regulated by a variety of mediators released during the inflammatory process preceding the tumour appearance, but the role of inflammation in the development of bladder cancer is ambiguous. This study was designed around the hypothesis that sphingosine-1-phosphate (S1P), as a regulator of several cellular processes important in both inflammation and cancer development, may exert some of the pro-tumorigenic effects indirectly due to its ability to regulate the expression of human cathelicidin (hCAP-18). LL-37 peptide released from hCAP-18 is involved in the development of various types of cancer in humans, especially those associated with infections. Using immunohistological staining, we showed high expression of hCAP-18/LL-37 and sphingosine kinase 1 (the enzyme that forms S1P from sphingosine) in human bladder cancer cells. In a cell culture model, S1P was able to stimulate the expression and release of hCAP-18/LL-37 from human bladder cells, and the addition of LL-37 peptide dose-dependently increased their proliferation. Additionally, the effect of S1P on LL-37 release was inhibited in the presence of FTY720P, a synthetic immunosuppressant that blocks S1P receptors. Together, this study presents the possibility of paracrine relation in which LL-37 production following cell stimulation by S1P promotes the development and growth of bladder cancer.
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Affiliation(s)
- Tomasz Wollny
- Holy Cross Oncology Center of Kielce, Artwińskiego 3, 25-734 Kielce, Poland; (T.W.); (K.G.); (S.G.); (J.K.)
| | - Urszula Wnorowska
- Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland; (U.W.); (Ł.S.)
| | - Ewelina Piktel
- Independent Laboratory of Nanomedicine, Medical University of Bialystok, Mickiewicza 2B, 15-222 Bialystok, Poland;
| | - Łukasz Suprewicz
- Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland; (U.W.); (Ł.S.)
| | - Grzegorz Król
- Department of Microbiology and Immunology, Institute of Medical Science, Collegium Medicum, Jan Kochanowski University of Kielce, IX Wieków Kielc 19A, 25-317 Kielce, Poland;
| | - Katarzyna Głuszek
- Holy Cross Oncology Center of Kielce, Artwińskiego 3, 25-734 Kielce, Poland; (T.W.); (K.G.); (S.G.); (J.K.)
| | - Stanisław Góźdź
- Holy Cross Oncology Center of Kielce, Artwińskiego 3, 25-734 Kielce, Poland; (T.W.); (K.G.); (S.G.); (J.K.)
- Department of Microbiology and Immunology, Institute of Medical Science, Collegium Medicum, Jan Kochanowski University of Kielce, IX Wieków Kielc 19A, 25-317 Kielce, Poland;
| | - Janusz Kopczyński
- Holy Cross Oncology Center of Kielce, Artwińskiego 3, 25-734 Kielce, Poland; (T.W.); (K.G.); (S.G.); (J.K.)
| | - Robert Bucki
- Department of Medical Microbiology and Nanobiomedical Engineering, Medical University of Bialystok, Mickiewicza 2C, 15-222 Bialystok, Poland; (U.W.); (Ł.S.)
- Department of Microbiology and Immunology, Institute of Medical Science, Collegium Medicum, Jan Kochanowski University of Kielce, IX Wieków Kielc 19A, 25-317 Kielce, Poland;
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22
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Can We Mitigate Coronary Heart Disease Risk in Patients with Cancer? Curr Atheroscler Rep 2022; 24:599-606. [PMID: 35624391 DOI: 10.1007/s11883-022-01035-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/06/2022] [Indexed: 11/03/2022]
Abstract
PURPOSE OF REVIEW The review focuses on the shared risk factors observed between coronary heart disease and cancer, cancer therapeutics causing coronary heart disease, and potential strategies to mitigate atherosclerosis in patients with cancer. RECENT FINDINGS The pathophysiology behind how traditional cardiovascular risk factors also contribute to cancer development and mortality is increasingly recognized. In addition, newer cancer therapies, such as immune checkpoint inhibitors, cause increased inflammation leading to increased cardiovascular events. Traditional coronary heart disease risk factors such as obesity, hypertension, diabetes, and hyperlipidemia also contribute to cancer development and worse cancer outcomes. Cancer therapeutics can also lead to atherosclerotic events in addition to the shared risk factors present at the time of cancer diagnosis. Understanding the pathophysiology, using multidisciplinary care teams, and developing machine learning algorithms for individualized patient care will help to mitigate the risk of coronary heart disease in patients with cancer.
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23
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Assis JLD, Fernandes AM, Aniceto BS, Fernandes da Costa PP, Banchio C, Girardini J, Vieyra A, Valverde RRHF, Einicker‐Lamas M. Sphingosine 1‐Phosphate Prevents Human Embryonic Stem Cell Death Following Ischemic Injury. EUR J LIPID SCI TECH 2022. [DOI: 10.1002/ejlt.202200019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022]
Affiliation(s)
- Juliane L. de Assis
- Laboratório de Biomembranas Instituto de Biofísica Carlos Chagas Filho–Universidade Federal do Rio de Janeiro Rio de Janeiro Brazil
| | - Aline M. Fernandes
- Laboratório de Biomembranas Instituto de Biofísica Carlos Chagas Filho–Universidade Federal do Rio de Janeiro Rio de Janeiro Brazil
| | - Bárbara S. Aniceto
- Laboratório de Biomembranas Instituto de Biofísica Carlos Chagas Filho–Universidade Federal do Rio de Janeiro Rio de Janeiro Brazil
| | - Pedro P. Fernandes da Costa
- Laboratório de Biomembranas Instituto de Biofísica Carlos Chagas Filho–Universidade Federal do Rio de Janeiro Rio de Janeiro Brazil
| | - Claudia Banchio
- Instituto de Biologia Molecular y Celular de Rosário Rosário Argentina
| | - Javier Girardini
- Instituto de Biologia Molecular y Celular de Rosário Rosário Argentina
| | - Adalberto Vieyra
- Laboratório de Físico‐Química Biológica Instituto de Biofísica Carlos Chagas Filho–Universidade Federal do Rio de Janeiro Rio de Janeiro Brazil
| | - Rafael R. H. F. Valverde
- Laboratório de Biomembranas Instituto de Biofísica Carlos Chagas Filho–Universidade Federal do Rio de Janeiro Rio de Janeiro Brazil
| | - Marcelo Einicker‐Lamas
- Laboratório de Biomembranas Instituto de Biofísica Carlos Chagas Filho–Universidade Federal do Rio de Janeiro Rio de Janeiro Brazil
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Qu L, Shi K, Xu J, Liu C, Ke C, Zhan X, Xu K, Liu Y. Atractylenolide-1 targets SPHK1 and B4GALT2 to regulate intestinal metabolism and flora composition to improve inflammation in mice with colitis. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 98:153945. [PMID: 35114452 DOI: 10.1016/j.phymed.2022.153945] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 01/10/2022] [Accepted: 01/13/2022] [Indexed: 06/14/2023]
Abstract
BACKGROUND Atractylenolide-1, an active component of Atractylodes Lancea, which is widely used to improve the gastrointestinal function. However, the efficacy and mechanism remain unclear in treating ulcerative colitis (UC). PURPOSE This study aimed to investigate the efficacy and the underlying mechanism of atractylenolide-1in UC. METHODS A dextran sulfate sodium (DSS)-induced UC mouse model was used to investigate the efficacy of atractylenolide-1. 16S DNA sequencing, GC-MS technique and transcriptome sequencing were used to detect the composition of mouse intestinal flora, the changes of metabolites and gene expression in mouse intestine. Compound-reaction-enzyme-gene network was used to find drug targets. Recombinant plasmid overexpression was used to verify drug targets in DSS mouse models. RESULTS The results showed that Atractylenolide-1 could significantly improve weight loss, diarrhea, blood in the stool, shortening of the colon, the loss of colonic goblet cells, reduction in mucoprotein MUC2, and tight junction proteins (zo-1, occludin) in mice with colitis. It reduced the inflammatory factors TNF-α, IL-6, IL-1β as well. The 16S sequencing showed that Atractylenolide-1 regulated the diversity and abundance of the intestinal flora in mice with colitis, and the analysis of flora enrichment indicated that the regulation of intestinal flora by atractylenolide-1 may be related to the regulation of metabolism. Correlation analysis of metabolomics and transcriptome showed that two genes SPHK1 and B4GALT2 related to the metabolism of fructose and galactose were regulated by atractylenolide-1. Further verification showed that atractylenolide-1 significantly inhibited the aberrance of SPHK1 and B4GALT2 in the colon with colitis. Meanwhile, it inhibited the activation of the PI3K-AKT pathway. SPHK1 and B4GALT2 overexpressing reversed the therapeutic effect of atractylenolide-1 in mice with colitis. CONCLUSION Atractylenolide-1 is a potential drug for the treatment of colitis by suppressing inflammation via the SPHK1/PI3K/AKT axis and by targeting SPHK1 and B4GAT2 to regulate fructose/galactose-related metabolism, thereby regulating the composition of the intestinal flora.
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Affiliation(s)
- Linghang Qu
- College of pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China
| | - Kun Shi
- College of pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China
| | - Jing Xu
- College of pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China
| | - Chunlian Liu
- College of pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China
| | - Chang Ke
- College of pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China
| | - Xin Zhan
- College of pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China
| | - Kang Xu
- College of pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China; Center for Hubei TCM processing technology engineering, Wuhan 430065, China.
| | - Yanju Liu
- College of pharmacy, Hubei University of Chinese Medicine, Wuhan 430065, China; Center for Hubei TCM processing technology engineering, Wuhan 430065, China.
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25
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Techarang T, Jariyapong P, Punsawad C. Role of sphingosine kinase and sphingosine-1-phosphate receptor in the liver pathology of mice infected with Plasmodium berghei ANKA. PLoS One 2022; 17:e0266055. [PMID: 35333897 PMCID: PMC8956183 DOI: 10.1371/journal.pone.0266055] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Accepted: 03/14/2022] [Indexed: 11/19/2022] Open
Abstract
Decreased serum sphingosine 1-phosphate (S1P) has been reported in severe malaria patients, but the expression of receptors and enzymes associated with S1P has not been investigated in the liver of malaria patients. Therefore, this study aimed to investigate the expression of sphingosine kinase (SphK) and S1P receptors (S1PRs) in the liver of malaria-infected mice. C57BL/6 male mice were divided into a control group (n = 10) and a Plasmodium berghei (PbA)-infected group (n = 10). Mice in the malaria group were intraperitoneally injected with 1×106 P. berghei ANKA-infected red blood cells, whereas control mice were intraperitoneally injected with normal saline. Liver tissues were collected on Day 13 of the experiment to evaluate histopathological changes by hematoxylin and eosin staining and to investigate SphK and S1PR expression by immunohistochemistry and real-time PCR. Histological examination of liver tissues from the PbA-infected group revealed sinusoidal dilatation, hemozoin deposition, portal tract inflammation and apoptotic hepatocytes, which were absent in the control group. Immunohistochemical staining showed significant increases in the expression of SphK1 and SphK2 and significant decreases in the expression of S1PR1, S1PR2, and S1PR3 in the endothelium, hepatocytes, and Kupffer cells in liver tissue from the PbA-infected group compared with the control group. Real-time PCR analysis showed the upregulation of SphK1 and the downregulation of S1PR1, S1PR2, and S1PR3 in the liver in the PbA-infected group compared with the control group. In conclusion, this study demonstrates for the first time that SphK1 mRNA expression is upregulated and that S1PR1, S1PR2, and S1PR3 expression is decreased in the liver tissue of PbA-infected mice. Our findings suggest that the decreased levels of S1PR1, S1PR2, and S1PR3 might play an important role in liver injury during malaria infection.
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Affiliation(s)
- Tachpon Techarang
- Department of Medical Science, School of Medicine, Walailak University, Nakhon Si Thammarat, Thailand
| | - Pitchanee Jariyapong
- Department of Medical Science, School of Medicine, Walailak University, Nakhon Si Thammarat, Thailand
| | - Chuchard Punsawad
- Department of Medical Science, School of Medicine, Walailak University, Nakhon Si Thammarat, Thailand
- Research Center in Tropical Pathobiology, Walailak University, Nakhon Si Thammarat, Thailand
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Sphingosine 1-Phosphate-Upregulated COX-2/PGE2 System Contributes to Human Cardiac Fibroblast Apoptosis: Involvement of MMP-9-Dependent Transactivation of EGFR Cascade. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:7664290. [PMID: 35242277 PMCID: PMC8888119 DOI: 10.1155/2022/7664290] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 01/11/2022] [Accepted: 01/12/2022] [Indexed: 12/20/2022]
Abstract
Human cardiac fibroblasts (HCFs) play key roles in normal physiological functions and pathological processes in the heart. Our recent study has found that, in HCFs, sphingosine 1-phosphate (S1P) can upregulate the expression of cyclooxygenase-2 (COX-2) leading to prostaglandin E2 (PGE2) generation mediated by S1P receptors/PKCα/MAPKs cascade-dependent activation of NF-κB. Alternatively, G protein-coupled receptor- (GPCR-) mediated transactivation of receptor tyrosine kinases (RTKs) has been proved to induce inflammatory responses. However, whether GPCR-mediated transactivation of RTKs participated in the COX-2/PGE2 system induced by S1P is still unclear in HCFs. We hypothesize that GPCR-mediated transactivation of RTKs-dependent signaling cascade is involved in S1P-induced responses. This study is aimed at exploring the comprehensive mechanisms of S1P-promoted COX-2/PGE2 expression and apoptotic effects on HCFs. Here, we used pharmacological inhibitors and transfection with siRNA to evaluate whether matrix metalloprotease (MMP)2/9, heparin-binding- (HB-) epidermal growth factor (EGF), EGF receptor (EGFR), PI3K/Akt, MAPKs, and transcription factor AP-1 participated in the S1P-induced COX-2/PGE2 system determined by Western blotting, real-time polymerase chain reaction (RT-PCR), chromatin immunoprecipitation (ChIP), and promoter-reporter assays in HCFs. Our results showed that S1PR1/3 activated by S1P coupled to Gq- and Gi-mediated MMP9 activity to stimulate EGFR/PI3K/Akt/MAPKs/AP-1-dependent activity of transcription to upregulate COX-2 accompanied with PGE2 production, leading to stimulation of caspase-3 activity and apoptosis. Moreover, S1P-enhanced c-Jun bound to COX-2 promoters on its corresponding binding sites, which was attenuated by these inhibitors of protein kinases, determined by a ChIP assay. These results concluded that transactivation of MMP9/EGFR-mediated PI3K/Akt/MAPKs-dependent AP-1 activity was involved in the upregulation of the COX-2/PGE2 system induced by S1P, in turn leading to apoptosis in HCFs.
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Associations among S100A4, Sphingosine-1-Phosphate, and Pulmonary Function in Patients with Chronic Obstructive Pulmonary Disease. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2022; 2022:6041471. [PMID: 35165531 PMCID: PMC8837900 DOI: 10.1155/2022/6041471] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Revised: 12/12/2021] [Accepted: 01/13/2022] [Indexed: 12/26/2022]
Abstract
Background. S100A4 is a member of the S100 calcium-binding protein family and is increased in patients with chronic obstructive pulmonary disease (COPD). Sphingosine-1-phosphate (S1P) is a naturally occurring bioactive sphingolipid, which regulates the adhesion between the cells and the extracellular matrix and affects cell migration and differentiation. The goal of this study was to analyze the correlations among S100A4, S1P, and pulmonary function among COPD patients. Methods. All 139 serum samples and 15 lung specimens were collected in COPD patients and control subjects. S100A4 and S1P were detected in two groups. The markers of fibrosis and epithelial-mesenchymal transition (EMT) were measured in the lungs of COPD patients and control subjects. Results. The protein expression of S100A4 was higher in the lungs and serum of COPD patients than control cases. Additionally, serum S100A4 was inversely associated with pulmonary function among COPD patients. Meanwhile, collagen deposition and EMT nuclear transcription factors were elevated in the lungs of COPD patients. Moreover, the protein expression of S1P was increased in the serum of COPD patients. Serum S1P was gradually increased along with pulmonary function decline in COPD patients. Further correlation analysis revealed that serum S1P was negatively associated with pulmonary function in COPD patients. Furthermore, there was a positive correlation between S1P and S100A4 in COPD patients. Conclusions. These results provide evidence that the elevation of S100A4 and S1P may be involved in the onset and progression of COPD.
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Dai L, Wang C, Wang W, Song K, Ye T, Zhu J, Di W. Activation of SphK2 contributes to adipocyte-induced EOC cell proliferation. Open Med (Wars) 2022; 17:229-238. [PMID: 35178477 PMCID: PMC8812714 DOI: 10.1515/med-2022-0422] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Revised: 12/11/2021] [Accepted: 12/14/2021] [Indexed: 11/27/2022] Open
Abstract
Epithelial ovarian cancer (EOC) is the leading cause of deaths due to cancer in women. Adipocytes have been suggested to play a key role in the stimulation of EOC growth. However, the mechanisms underlying the adipocyte-induced EOC proliferation remain undefined. Here, we provide the first evidence that adipocytes induce the activation of sphingosine kinase (SphK) 2 in EOC, which represents a novel pathway that mediates the adipocyte-induced EOC growth. SphK2 inhibition in EOC cells led to a remarkable inhibition of the adipocyte-induced cell proliferation. Moreover, the adipocyte-induced SphK2 activation in EOC cells was extracellular signal-regulated protein kinases (ERK) dependent. Furthermore, silencing SphK2 in EOC significantly inhibited the adipocyte-induced expression of phospho-ERK and c-Myc, two crucial players in EOC growth. Collectively, the current study unraveled a previously unrecognized role of SphK2 in the adipocyte-induced growth-promoting action in EOC, suggesting a novel target for EOC treatment.
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Affiliation(s)
- Lan Dai
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 200127 , China
- Department of Cell Biology, Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 200127 , China
| | - Chen Wang
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 200127 , China
- Department of Cell Biology, Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 200127 , China
| | - Wenjing Wang
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 200127 , China
- Department of Cell Biology, Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 200127 , China
| | - Keqi Song
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 200127 , China
- Department of Cell Biology, Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 200127 , China
| | - Taiyang Ye
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 200127 , China
- Department of Cell Biology, Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 200127 , China
| | - Jie Zhu
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 200127 , China
- Department of Cell Biology, Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 200127 , China
| | - Wen Di
- Department of Obstetrics and Gynecology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 200127 , China
- Department of Cell Biology, Shanghai Key Laboratory of Gynecologic Oncology, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University , Shanghai 200127 , China
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Xu G, Yang Z, Sun Y, Dong H, Ma J. Interaction of microRNAs with sphingosine kinases, sphingosine-1 phosphate, and sphingosine-1 phosphate receptors in cancer. Discov Oncol 2021; 12:33. [PMID: 35201458 PMCID: PMC8777508 DOI: 10.1007/s12672-021-00430-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 09/03/2021] [Indexed: 12/12/2022] Open
Abstract
Sphingosine-1-phosphate (S1P), a pleiotropic lipid mediator, participates in various cellular processes during tumorigenesis, including cell proliferation, survival, drug resistance, metastasis, and angiogenesis. S1P is formed by two sphingosine kinases (SphKs), SphK1 and SphK2. The intracellularly produced S1P is delivered to the extracellular space by ATP-binding cassette (ABC) transporters and spinster homolog 2 (SPNS2), where it binds to five transmembrane G protein-coupled receptors to mediate its oncogenic functions (S1PR1-S1PR5). MicroRNAs (miRNAs) are small non-coding RNAs, 21-25 nucleotides in length, that play numerous crucial roles in cancer, such as tumor initiation, progression, apoptosis, metastasis, and angiogenesis via binding to the 3'-untranslated region (3'-UTR) of the target mRNA. There is growing evidence that various miRNAs modulate tumorigenesis by regulating the expression of SphKs, and S1P receptors. We have reviewed various roles of miRNAs, SphKs, S1P, and S1P receptors (S1PRs) in malignancies and how notable miRNAs like miR-101, miR-125b, miR-128, and miR-506, miR-1246, miR-21, miR-126, miR499a, miR20a-5p, miR-140-5p, miR-224, miR-137, miR-183-5p, miR-194, miR181b, miR136, and miR-675-3p, modulate S1P signaling. These tumorigenesis modulating miRNAs are involved in different cancers including breast, gastric, hepatocellular carcinoma, prostate, colorectal, cervical, ovarian, and lung cancer via cell proliferation, invasion, angiogenesis, apoptosis, metastasis, immune evasion, chemoresistance, and chemosensitivity. Therefore, understanding the interaction of SphKs, S1P, and S1P receptors with miRNAs in human malignancies will lead to better insights for miRNA-based cancer therapy.
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Affiliation(s)
- Guangmeng Xu
- Department of Colorectal Surgery, The Second Hospital of Jilin University, Changchun, 130000 China
| | - Zecheng Yang
- Department of Gastrointestinal Surgery, The Second Hospital of Jilin University, Changchun, 130000 China
| | - Yamin Sun
- Department of Gastrointestinal Surgery, The Second Hospital of Jilin University, Changchun, 130000 China
| | - Hongmei Dong
- Department of Gastrointestinal Surgery, The Second Hospital of Jilin University, Changchun, 130000 China
| | - Jingru Ma
- Clinical Laboratory, The Second Hospital of Jilin University, Changchun, 130000 China
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30
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Caio G, Lungaro L, Chiarioni G, Giancola F, Caputo F, Guarino M, Volta U, Testino G, Pellicano R, Zoli G, DE Giorgio R. Beyond biologics: advanced therapies in inflammatory bowel diseases. Minerva Gastroenterol (Torino) 2021; 68:319-332. [PMID: 34309337 DOI: 10.23736/s2724-5985.21.02985-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Inflammatory bowel diseases (IBDs) are conditions characterized by persistent and relapsing inflammation involving the gastrointestinal tract at various levels. Although the etiopathogenesis of IBDs is partially understood, a deregulated activation of intestinal immune cells in genetically susceptible patients is thought to be key for the disease onset and evolution. Artificial Nutrition might affect favorably on inflammation and related cytokine storm. However, the discovery of monoclonal antibodies blocking pro-inflammatory cytokines (e.g., tumor necrosis factor-α - TNF-α) changed radically the management of IBDs. Anti-TNF-α agents represent the prototype molecule of the so-called 'biologics' / 'biologicals'. These compounds have significantly improved the therapeutic management of IBDs refractory to standard medications, achieving clinical remission, mucosal healing and preventing extra-intestinal manifestations. However, about 50% of patients treated with biologicals experienced drawbacks, such as primary failure or loss of response, requiring new effective treatments. Translational studies have identified other pathways, different from the TNF-α blockade, and new molecules, e.g. sphingosine-1-phosphate agonists and the JAK kinase inhibitors, have been proposed as potential therapeutic options for IBDs. These novel therapeutic approaches represent a "new era" of IBD management, especially for patients poorly responsive to biologicals. In this review, we will summarize the new pharmacological strategies to treat IBDs, and discuss their effectiveness and safety, along with future perspectives for IBD treatment.
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Affiliation(s)
- Giacomo Caio
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy.,Mucosal Immunology and Biology Research Center, Massachusetts General Hospital-Harvard Medical School, Boston, MA, USA.,Center for the Study and Treatment of Chronic Inflammatory Intestinal Diseases (IBD) and Gastroenterological Manifestations of Rare Diseases, Department of Translational Medicine, University of Ferrara, Ferrara, Italy.,Center for the Study and Treatment of Alcohol-Related Diseases, Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Lisa Lungaro
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy.,Department of Internal Medicine, Santissima Annunziata Hospital, University of Ferrara, Cento, Ferrara, Italy
| | - Giuseppe Chiarioni
- Division of Gastroenterology of the University of Verona, A.O.U.I. Verona, Verona, Italy.,Division of Gastroenterology and Hepatology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Fiorella Giancola
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Fabio Caputo
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy.,Center for the Study and Treatment of Chronic Inflammatory Intestinal Diseases (IBD) and Gastroenterological Manifestations of Rare Diseases, Department of Translational Medicine, University of Ferrara, Ferrara, Italy.,Center for the Study and Treatment of Alcohol-Related Diseases, Department of Translational Medicine, University of Ferrara, Ferrara, Italy.,Department of Internal Medicine, Santissima Annunziata Hospital, University of Ferrara, Cento, Ferrara, Italy
| | - Matteo Guarino
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy
| | - Umberto Volta
- Department of Medical and Surgical Sciences, University of Bologna, Bologna, Italy
| | - Gianni Testino
- Unit of Addiction and epatology/Alcohological Regional Centre, ASL3 c/o IRCCS San Martino Hospital, Genova, Italy.,Italian Society on Alcohol, Bologna, Italy
| | | | - Giorgio Zoli
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy.,Center for the Study and Treatment of Chronic Inflammatory Intestinal Diseases (IBD) and Gastroenterological Manifestations of Rare Diseases, Department of Translational Medicine, University of Ferrara, Ferrara, Italy.,Center for the Study and Treatment of Alcohol-Related Diseases, Department of Translational Medicine, University of Ferrara, Ferrara, Italy.,Department of Internal Medicine, Santissima Annunziata Hospital, University of Ferrara, Cento, Ferrara, Italy
| | - Roberto DE Giorgio
- Department of Translational Medicine, University of Ferrara, Ferrara, Italy - .,Center for the Study and Treatment of Chronic Inflammatory Intestinal Diseases (IBD) and Gastroenterological Manifestations of Rare Diseases, Department of Translational Medicine, University of Ferrara, Ferrara, Italy.,Center for the Study and Treatment of Alcohol-Related Diseases, Department of Translational Medicine, University of Ferrara, Ferrara, Italy
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Zheng H, Siddharth S, Parida S, Wu X, Sharma D. Tumor Microenvironment: Key Players in Triple Negative Breast Cancer Immunomodulation. Cancers (Basel) 2021; 13:cancers13133357. [PMID: 34283088 PMCID: PMC8269090 DOI: 10.3390/cancers13133357] [Citation(s) in RCA: 35] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Revised: 06/29/2021] [Accepted: 07/01/2021] [Indexed: 12/16/2022] Open
Abstract
Simple Summary The tumor microenvironment (TME) is a complicated network composed of various cells, signaling molecules, and extra cellular matrix. TME plays a crucial role in triple negative breast cancer (TNBC) immunomodulation and tumor progression, paradoxically, acting as an immunosuppressive as well as immunoreactive factor. Research regarding tumor immune microenvironment has contributed to a better understanding of TNBC subtype classification. Shall we treat patients precisely according to specific subtype classification? Moving beyond traditional chemotherapy, multiple clinical trials have recently implied the potential benefits of immunotherapy combined with chemotherapy. In this review, we aimed to elucidate the paradoxical role of TME in TNBC immunomodulation, summarize the subtype classification methods for TNBC, and explore the synergistic mechanism of chemotherapy plus immunotherapy. Our study may provide a new direction for the development of combined treatment strategies for TNBC. Abstract Triple negative breast cancer (TNBC) is a heterogeneous disease and is highly related to immunomodulation. As we know, the most effective approach to treat TNBC so far is still chemotherapy. Chemotherapy can induce immunogenic cell death, release of damage-associated molecular patterns (DAMPs), and tumor microenvironment (TME) remodeling; therefore, it will be interesting to investigate the relationship between chemotherapy-induced TME changes and TNBC immunomodulation. In this review, we focus on the immunosuppressive and immunoreactive role of TME in TNBC immunomodulation and the contribution of TME constituents to TNBC subtype classification. Further, we also discuss the role of chemotherapy-induced TME remodeling in modulating TNBC immune response and tumor progression with emphasis on DAMPs-associated molecules including high mobility group box1 (HMGB1), exosomes, and sphingosine-1-phosphate receptor 1 (S1PR1), which may provide us with new clues to explore effective combined treatment options for TNBC.
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Affiliation(s)
- Hongmei Zheng
- Hubei Provincial Clinical Research Center for Breast Cancer, Department of Breast Surgery, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430079, China
- The Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA; (S.S.); (S.P.); (D.S.)
- Correspondence: (H.Z.); (X.W.)
| | - Sumit Siddharth
- The Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA; (S.S.); (S.P.); (D.S.)
| | - Sheetal Parida
- The Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA; (S.S.); (S.P.); (D.S.)
| | - Xinhong Wu
- Hubei Provincial Clinical Research Center for Breast Cancer, Department of Breast Surgery, Hubei Cancer Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430079, China
- Correspondence: (H.Z.); (X.W.)
| | - Dipali Sharma
- The Sidney Kimmel Comprehensive Cancer Center, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA; (S.S.); (S.P.); (D.S.)
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32
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Nema R, Kumar A. Sphingosine-1-Phosphate Catabolizing Enzymes Predict Better Prognosis in Triple-Negative Breast Cancer Patients and Correlates With Tumor-Infiltrating Immune Cells. Front Mol Biosci 2021; 8:697922. [PMID: 34235182 PMCID: PMC8255376 DOI: 10.3389/fmolb.2021.697922] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Accepted: 06/04/2021] [Indexed: 02/05/2023] Open
Abstract
Background: Triple-negative breast cancer (TNBC) is associated with a poor prognosis. Sphingosine-1-phosphate (S1P), a potent sphingolipid metabolite, has been implicated in many processes that are important for breast cancer (BC). S1P signaling regulates tumorigenesis, and response to chemotherapy and immunotherapy by affecting the trafficking, differentiation or effector function of tumor-infiltrating immune cells (TIICs). Objective: In this study, using bioinformatics tools and publicly available databases, we have analyzed the prognostic value of S1P metabolizing genes and their correlation with TIICs in BC patients. Methods: The expression of S1P metabolizing genes and receptors was evaluated by the UALCAN cancer database. The correlation between mRNA expression of S1P metabolizing genes and receptors and survival outcome of breast cancer patients was analyzed by the Kaplan-Meier plotter database. The association between the gene expression and infiltration of immune cells in the tumors was analyzed by "Tumor-Infiltrating Immune Estimation Resource (TIMER). In silico protein expression analysis was done using the Human Protein Atlas" database. Results: TNBC patients with lower expression of S1P phosphatase 1 (SGPP1) or lipid phosphate phosphatase 3 (PLPP3) have much shorter relapse-free survival than the patients with a higher expression of these genes. SGPP1 and PLPP3 expression show a strong positive correlation with tumor-infiltrating dendritic cells (DCs), CD4+ and CD8+ T cells, neutrophils, and macrophages in the TNBC subtypes. In addition, S1P receptor 4 (S1PR4), an S1P receptor exhibit a strong positive correlation with DCs, CD4+ and CD8+ T cells and neutrophils in TNBC. We, therefore, conclude that low expression of SGPP1 and PLPP3 may hinder the recruitment of immune cells to the tumor environment, resulting in the blockage of cancer cell clearance and a subsequent poor prognosis.
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Affiliation(s)
| | - Ashok Kumar
- Department of Biochemistry, All India Institute of Medical Sciences (AIIMS) Bhopal, Bhopal, India
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33
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Sukocheva OA, Hu DG, Meech R, Bishayee A. Divergence of Intracellular Trafficking of Sphingosine Kinase 1 and Sphingosine-1-Phosphate Receptor 3 in MCF-7 Breast Cancer Cells and MCF-7-Derived Stem Cell-Enriched Mammospheres. Int J Mol Sci 2021; 22:4314. [PMID: 33919234 PMCID: PMC8122545 DOI: 10.3390/ijms22094314] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2021] [Revised: 04/11/2021] [Accepted: 04/19/2021] [Indexed: 02/05/2023] Open
Abstract
Breast cancer MCF-7 cell-line-derived mammospheres were shown to be enriched in cells with a CD44+/CD24- surface profile, consistent with breast cancer stem cells (BCSC). These BCSC were previously reported to express key sphingolipid signaling effectors, including pro-oncogenic sphingosine kinase 1 (SphK1) and sphingosine-1-phosphate receptor 3 (S1P3). In this study, we explored intracellular trafficking and localization of SphK1 and S1P3 in parental MCF-7 cells, and MCF-7 derived BCSC-enriched mammospheres treated with growth- or apoptosis-stimulating agents. Intracellular trafficking and localization were assessed using confocal microscopy and cell fractionation, while CD44+/CD24- marker status was confirmed by flow cytometry. Mammospheres expressed significantly higher levels of S1P3 compared to parental MCF-7 cells (p < 0.01). Growth-promoting agents (S1P and estrogen) induced SphK1 and S1P3 translocation from cytoplasm to nuclei, which may facilitate the involvement of SphK1 and S1P3 in gene regulation. In contrast, pro-apoptotic cytokine tumor necrosis factor α (TNFα)-treated MCF-7 cells demonstrated increased apoptosis and no nuclear localization of SphK1 and S1P3, suggesting that TNFα can inhibit nuclear translocation of SphK1 and S1P3. TNFα inhibited mammosphere formation and induced S1P3 internalization and degradation. No nuclear translocation of S1P3 was detected in TNFα-stimulated mammospheres. Notably, SphK1 and S1P3 expression and localization were highly heterogenous in mammospheres, suggesting the potential for a large variety of responses. The findings provide further insights into the understanding of sphingolipid signaling and intracellular trafficking in BCs. Our data indicates that the inhibition of SphK1 and S1P3 nuclear translocation represents a novel method to prevent BCSCs proliferation.
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Affiliation(s)
- Olga A. Sukocheva
- Discipline of Health Sciences, College of Nursing and Health Sciences, Flinders University of South Australia, Bedford Park, South Australia 5042, Australia
| | - Dong Gui Hu
- Department of Clinical Pharmacology, College of Medicine and Public Health, Flinders University of South Australia, Bedford Park, South Australia 5042, Australia; (D.G.H.); (R.M.)
| | - Robyn Meech
- Department of Clinical Pharmacology, College of Medicine and Public Health, Flinders University of South Australia, Bedford Park, South Australia 5042, Australia; (D.G.H.); (R.M.)
| | - Anupam Bishayee
- Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA
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34
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Khoei SG, Sadeghi H, Samadi P, Najafi R, Saidijam M. Relationship between Sphk1/S1P and microRNAs in human cancers. Biotechnol Appl Biochem 2021; 68:279-287. [PMID: 32275078 DOI: 10.1002/bab.1922] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2020] [Accepted: 04/04/2020] [Indexed: 12/12/2022]
Abstract
Sphingosine kinases type 1 (SphK1) is a key enzyme in the phosphorylation of sphingosine to sphingosine 1-phosphate (S1P). Different abnormalities in SphK1 functions may correspond with poor prognosis in various cancers. Additionally, upregulated SphK1/S1P could promote cancer cell proliferation, angiogenesis, mobility, invasion, and metastasis. MicroRNAs as conserved small noncoding RNAs play major roles in cancer initiation, progression, metastasis, etc. Their posttranscriptionally mechanisms could affect the development of cancer growth or tumorigenesis suppression. The growing number of studies has described that various microRNAs can be regulated by SphK1, and its expression level can also be regulated by microRNAs. In this review, the relationship of SphK1 and microRNA functions and their interaction in human malignancies have been discussed. Based on them novel treatment strategies can be introduced.
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Affiliation(s)
- Saeideh Gholamzadeh Khoei
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Student Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Hamid Sadeghi
- Department of Microbiology and Virology, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Pouria Samadi
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
- Student Research Committee, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Rezvan Najafi
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
| | - Massoud Saidijam
- Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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Paliwal D, Srivastava S, Sharma PK, Ahmad I. Marine Originated Fused Heterocyclic: Prospective Bioactivity against Cancer. CURRENT TRADITIONAL MEDICINE 2021. [DOI: 10.2174/2215083805666190328205729] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
The deep Sea has several herbal sources such as marine organisms. These marine
sources possibly have effective anticancer properties. The fused heterocyclic ring with marine
source has special characteristics with minimum toxicity and with maximum anticancer
effects. The review focused on and classified the prospective lead compounds which have
shown a promising therapeutic range as anticancer agents in clinical and preclinical trials.
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Affiliation(s)
- Deepika Paliwal
- Department of Pharmacy, School of Medical & Allied Sciences, Galgotias University, Greater Noida, 201310, India
| | - Saurabh Srivastava
- Department of Oral & Maxillofacial Surgery, King George’s Medical University, Lucknow, UP 226003, India
| | - Pramod Kumar Sharma
- Department of Pharmacy, School of Medical & Allied Sciences, Galgotias University, Greater Noida, 201310, India
| | - Irfan Ahmad
- Department of Clinical Laboratory Science, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
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Wang X, Yang G. Bone marrow mesenchymal stem cells-derived exosomes reduce Aβ deposition and improve cognitive function recovery in mice with Alzheimer's disease by activating sphingosine kinase/sphingosine-1-phosphate signaling pathway. Cell Biol Int 2021; 45:775-784. [PMID: 33300254 DOI: 10.1002/cbin.11522] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2020] [Revised: 10/09/2020] [Accepted: 12/06/2020] [Indexed: 12/21/2022]
Abstract
Exosomes are associated with the development and progression of Alzheimer's disease (AD), although the impact of these extracellular vesicles in brain pathological condition remains incompletely understood. Therefore, this study aimed to investigate the role and mechanism of exosomes signaling in AD. Double transgenic APP/PS1 mice were injected with bone marrow mesenchymal stem cells (BM-MSCs)-derived exosomes or combined with SKI-Ⅱ (sphingosine kinase [SphK] inhibitor) or VPC23019 (sphingosine-1-phosphate [S1P] 1 receptor blocker). We observed the spatial learning and memory ability of mice, and assessed the levels of amyloid and proteins. We found that exosomes improved spatial learning and memory ability of APP/PS1 mice, and enhanced the expression of SphK1 and S1P1. Moreover, exosomes inhibited the levels of amyloid and enhanced the expression of NeuN in cortex and hippocampus of APP/PS1 mice. Exosomes repressed the levels of Aβ1-40, Aβ1-42, BACE1, and PS1, and promoted the expression of neprilysin in APP/PS1 mice. The influence conferred by exosomes was abolished by SKI-Ⅱ or VPC23019. In conclusion, our article confirms that BM-MSCs-derived exosomes reduce Aβ deposition and promote cognitive function recovery in AD mice by activating SphK/S1P signaling pathway. Thus, our data suggest that S1P/SphK-containing exosomes should be explored as potential AD cure.
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Affiliation(s)
- Xinhui Wang
- Department of Geriatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.,Department of Geriatrics, Henan Provincial People's Hospital, People's Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Guojie Yang
- Department of Geriatrics, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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Anwar M, Mehta D. Post-translational modifications of S1PR1 and endothelial barrier regulation. Biochim Biophys Acta Mol Cell Biol Lipids 2020; 1865:158760. [PMID: 32585303 PMCID: PMC7409382 DOI: 10.1016/j.bbalip.2020.158760] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 06/09/2020] [Accepted: 06/15/2020] [Indexed: 12/16/2022]
Abstract
Sphingosine-1-phosphate receptor-1 (S1PR1), a G-protein coupled receptor that is expressed in endothelium and activated upon ligation by the bioactive lipid sphingosine-1-phosphate (S1P), is an important vascular-barrier protective mechanism at the level of adherens junctions (AJ). Loss of endothelial barrier function is a central factor in the pathogenesis of various inflammatory conditions characterized by protein-rich lung edema formation, such as acute respiratory distress syndrome (ARDS). While several S1PR1 agonists are available, the challenge of arresting the progression of protein-rich edema formation remains to be met. In this review, we discuss the role of S1PRs, especially S1PR1, in regulating endothelial barrier function. We review recent findings showing that replenishment of the pool of cell-surface S1PR1 may be crucial to the effectiveness of S1P in repairing the endothelial barrier. In this context, we discuss the S1P generating machinery and mechanisms that regulate S1PR1 at the cell surface and their impact on endothelial barrier function.
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Affiliation(s)
- Mumtaz Anwar
- Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois at Chicago Chicago, IL 60612, United States of America
| | - Dolly Mehta
- Department of Pharmacology and Center for Lung and Vascular Biology, University of Illinois at Chicago Chicago, IL 60612, United States of America.
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38
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Zhong L, Xie L, Yang Z, Li L, Song S, Cao D, Liu Y. Prognostic value of S1PR1 and its correlation with immune infiltrates in breast and lung cancers. BMC Cancer 2020; 20:766. [PMID: 32799825 PMCID: PMC7429796 DOI: 10.1186/s12885-020-07278-2] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2020] [Accepted: 08/09/2020] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Sphingosine-1-phosphate receptor (S1PR1) is involved in vascular development, a key process in tumorigenesis. This study aimed to evaluate its roles in tumor development and prognosis. METHODS S1PR1 expression levels were analyzed using TIMER and Oncomine database, and the prognostic significance of S1PR1 was assessed using PrognoScan and Kaplan-Meier plotter databases. The relationship between S1PR1 and tumor-infiltrated immune cells was analyzed using TIMER. RESULTS S1PR1 expression was remarkably lower in breast and lung cancer tissues than in the corresponding normal tissues. Lower expression was related to poor overall survival and disease-free survival in breast invasive carcinoma (BRCA), lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC). A functional network analysis confirmed the function of S1PR1 in regulating vasculogenesis. In addition, S1PR1 levels were significantly negative with regard to the tumor purity of BRCA (r = - 0.508, P = 1.76e-66), LUAD (r = - 0.353, P = 6.05e-16), and LUSC (r = - 0.402, P = - 5.20e-20). Furthermore, S1PR1 levels were significantly positive with regard to infiltrating CD8+ (r = 0.38, P = 5.91e-35) and CD4+ T cells (r = 0.335, P = 1.03e-26), macrophages (r = 0.219, P = 3.67e-12), neutrophils (r = 0.168, P = 2.03e-7), and dendritic cells (DCs) (r = 0.208, P = 9.14e-11) in BRCA; S1PR1 levels were significantly positive with regard to CD8+ T cells (r = 0.308, P = 3.61e-12), macrophages (r = 0.376, P = 1.01e-17), neutrophils (r = 0.246, P = 4.15e-8), and DCs (r = 0.207, P = 4.16e-6) in LUAD; and positive with regard to B cells (r = 0.356, P = 1.57e-15), CD8+ (r = 0.459, P = 3.83e-26) and CD4+ T cells (r = 0.338, P = 3.98e-14), macrophages (r = 0.566, P = 2.61e-45), neutrophils (r = 0.453, P = 1.79e-25), and DCs (r = 0.56, P = 2.12e-40) in LUSC. CONCLUSIONS S1PR1 levels are positively correlated with multiple immune markers in breast and lung cancer. These observed correlations between S1PR1 and the prognosis and immune cell infiltration provide a foundation for further research on its immunomodulatory role in cancer.
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Affiliation(s)
- Limei Zhong
- Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, No. 466 Xingang Middle Road, Haizhu District, Guangzhou, 510317, Guangdong Province, China
| | - Linling Xie
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, No. 16 Airport Road, Baiyun District, Guangzhou, 510407, China
| | - Zhiyong Yang
- Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, No. 466 Xingang Middle Road, Haizhu District, Guangzhou, 510317, Guangdong Province, China
| | - Lijuan Li
- Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, No. 466 Xingang Middle Road, Haizhu District, Guangzhou, 510317, Guangdong Province, China
| | - Shaohua Song
- Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, No. 466 Xingang Middle Road, Haizhu District, Guangzhou, 510317, Guangdong Province, China
| | - Donglin Cao
- Department of Laboratory Medicine, Guangdong Second Provincial General Hospital, No. 466 Xingang Middle Road, Haizhu District, Guangzhou, 510317, Guangdong Province, China.
| | - Yufeng Liu
- The First Affiliated Hospital, Guangzhou University of Chinese Medicine, No. 16 Airport Road, Baiyun District, Guangzhou, 510407, China.
- Lingnan Medical Research Center, Guangzhou University of Chinese Medicine, Guangzhou, 510407, China.
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Inhibitors of Ceramide- and Sphingosine-Metabolizing Enzymes as Sensitizers in Radiotherapy and Chemotherapy for Head and Neck Squamous Cell Carcinoma. Cancers (Basel) 2020; 12:cancers12082062. [PMID: 32722626 PMCID: PMC7463798 DOI: 10.3390/cancers12082062] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2020] [Revised: 07/21/2020] [Accepted: 07/23/2020] [Indexed: 02/07/2023] Open
Abstract
In the treatment of advanced head and neck squamous cell carcinoma (HNSCC), including oral SCC, radiotherapy is a commonly performed therapeutic modality. The combined use of radiotherapy with chemotherapy improves therapeutic effects, but it also increases adverse events. Ceramide, a central molecule in sphingolipid metabolism and signaling pathways, mediates antiproliferative responses, and its level increases in response to radiotherapy and chemotherapy. However, when ceramide is metabolized, prosurvival factors, such as sphingosine-1-phosphate (S1P), ceramide-1-phosphate (C1P), and glucosylceramide, are produced, reducing the antitumor effects of ceramide. The activities of ceramide- and sphingosine-metabolizing enzymes are also associated with radio- and chemo-resistance. Ceramide analogs and low molecular-weight compounds targeting these enzymes exert anticancer effects. Synthetic ceramides and a therapeutic approach using ultrasound have also been developed. Inhibitors of ceramide- and sphingosine-metabolizing enzymes and synthetic ceramides can function as sensitizers of radiotherapy and chemotherapy for HNSCC.
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40
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Zhou H, Yin X, Bai F, Liu W, Jiang S, Zhao J. The Role and Mechanism of S1PR5 in Colon Cancer. Cancer Manag Res 2020; 12:4759-4775. [PMID: 32606966 PMCID: PMC7311188 DOI: 10.2147/cmar.s239118] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Accepted: 05/12/2020] [Indexed: 12/12/2022] Open
Abstract
Purpose To investigate the role and mechanism of S1PR5 in colon cancer. Materials and Methods Lentiviral infection and drug screening helped to establish colon cancer cell lines with stable overexpression and knockdown of S1PR5. Effects of S1PR5 expression on cell growth, proliferation, migration, and invasion were analyzed using a subcutaneous xenograft model in nude mice. Western blot (WB) was used to detect the effects of S1PR5 expression on p-AKT, STAT3, NF-κB, and p-JNK. The distribution of p65 was evaluated in nuclear and cytoplasmic fractions using WB. CCK-8, Transwell migration, and Transwell invasion assays analyzed cell growth, proliferation, migration, and invasion. qRT-PCR analysis revealed that S1PR5 expression was associated with altered expression levels of NF-κB downstream target genes, such as IL-6, TNF-α, and indoleamine 2, 3-dioxygenase 1 (IDO1). Results qRT-PCR and WB analysis showed that the S1PR5 level in colon cancer cell lines-SW480, SW620, HCT116, and LoVo-was significantly higher than in NCM460, a healthy colonic epithelial cell line. SW620 and SW480, with high and low expression of S1PR5, respectively, were selected as model cell lines. S1PR5 knockdown in SW620 caused the growth rate, proliferation, migration, invasion, and subcutaneous tumor formation rate to decrease in mice, whereas S1PR5 overexpression in SW480 caused all of these parameters to increase. WB analysis showed an increase in phospho-p65 and its nuclear translocation. S1PR5 knockdown caused a decrease in phospho-p65 levels and its nuclear import, thereby inhibiting its activity. In S1PR5 knockdown and overexpressing cells, p65 was overexpressed and knocked down, respectively. qRT-PCR and WB showed that S1PR5 over-expression up-regulates IDO1, and S1PR5 knockdown inhibits IDO1. CCK-8 and Transwell assays showed that p65 and IDO1 overexpression antagonizes the antitumor effect of S1PR5 knockdown, and that p65 and IDO1 knockdown antagonizes the tumorigenic effect of S1PR5 overexpression. Conclusion S1PR5 overexpression promotes the growth, migration, and invasion of cancer by activating the NF-κB/IDO1 signaling pathway.
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Affiliation(s)
- Huijun Zhou
- Key Laboratory of Nanobiological Technology of National Health Commission of China, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
| | - Xianli Yin
- Department of Gastroenterology and Urology, Hunan Cancer Hospital & the Affiliated Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, People's Republic of China
| | - Fei Bai
- Department of Gastroduodeno Pancreatic Surgery, Hunan Cancer Hospital & the Affiliated Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, People's Republic of China
| | - Wu Liu
- Department of Gastroenterology and Urology, Hunan Cancer Hospital & the Affiliated Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, People's Republic of China
| | - Shaofeng Jiang
- Department of Gastroenterology and Urology, Hunan Cancer Hospital & the Affiliated Hospital of Xiangya School of Medicine, Central South University, Changsha 410013, Hunan, People's Republic of China
| | - Jinfeng Zhao
- Key Laboratory of Nanobiological Technology of National Health Commission of China, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China
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Abstract
Sphingosine-1-phosphate (S1P) can regulate several physiological and pathological processes. S1P signaling via its cell surface receptor S1PR1 has been shown to enhance tumorigenesis and stimulate growth, expansion, angiogenesis, metastasis, and survival of cancer cells. S1PR1-mediated tumorigenesis is supported and amplified by activation of downstream effectors including STAT3, interleukin-6, and NF-κB networks. S1PR1 signaling can also trigger various other signaling pathways involved in carcinogenesis including activation of PI3K/AKT, MAPK/ERK1/2, Rac, and PKC/Ca, as well as suppression of cyclic adenosine monophosphate (cAMP). It also induces immunological tolerance in the tumor microenvironment, while the immunosuppressive function of S1PR1 can also lead to the generation of pre-metastatic niches. Some tumor cells upregulate S1PR1 signaling pathways, which leads to drug resistant cancer cells, mainly through activation of STAT3. This signaling pathway is also implicated in some inflammatory conditions leading to the instigation of inflammation-driven cancers. Furthermore, it can also increase survival via induction of anti-apoptotic pathways, for instance, in breast cancer cells. Therefore, S1PR1 and its signaling pathways can be considered as potential anti-tumor therapeutic targets, alone or in combination therapies. Given the oncogenic nature of S1PR1 and its distribution in a variety of cancer cell types along with its targeting advantages over other molecules of this family, S1PR1 should be considered a favorable target in therapeutic approaches to cancer. This review describes the role of S1PR1 in cancer development and progression, specifically addressing breast cancer, glioma, and hematopoietic malignancies. We also discuss the potential use of S1P signaling modulators as therapeutic targets in cancer therapy.
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42
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Zhang L, Dong Y, Wang Y, Hu W, Dong S, Chen Y. Sphingosine-1-phosphate (S1P) receptors: Promising drug targets for treating bone-related diseases. J Cell Mol Med 2020; 24:4389-4401. [PMID: 32155312 PMCID: PMC7176849 DOI: 10.1111/jcmm.15155] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2019] [Revised: 01/22/2020] [Accepted: 02/01/2020] [Indexed: 12/20/2022] Open
Abstract
Sphingosine-1-phosphate (S1P) is a natural bioactive lipid molecule and a common first or second messenger in the cardiovascular and immune systems. By binding with its receptors, S1P can serve as mediator of signalling during cell migration, differentiation, proliferation and apoptosis. Although the predominant role of S1P in bone regeneration has been noted in many studies, this role is not as well-known as its roles in the cardiovascular and immune systems. In this review, we summarize previous research on the role of S1P receptors (S1PRs) in osteoblasts and osteoclasts. In addition, S1P is regarded as a bridge between bone resorption and formation, which brings hope to patients with bone-related diseases. Finally, we discuss S1P and its receptors as therapeutic targets for treating osteoporosis, inflammatory osteolysis and bone metastasis based on the biological effects of S1P in osteoclastic/osteoblastic cells, immune cells and tumour cells.
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Affiliation(s)
- Lincheng Zhang
- Department of Biomedical Materials Science, Third Military Medical University (Army Medical University), Chongqing, China.,Battalion One of Basic Medical Sciences, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yutong Dong
- Department of Biomedical Materials Science, Third Military Medical University (Army Medical University), Chongqing, China.,Battalion One of Basic Medical Sciences, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yiran Wang
- Department of Biomedical Materials Science, Third Military Medical University (Army Medical University), Chongqing, China
| | - Wenhui Hu
- Department of Biomedical Materials Science, Third Military Medical University (Army Medical University), Chongqing, China
| | - Shiwu Dong
- Department of Biomedical Materials Science, Third Military Medical University (Army Medical University), Chongqing, China.,State Key Laboratory of Trauma, Burns and Combined Injury, Third Military Medical University (Army Medical University), Chongqing, China.,Department of Orthopedics, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
| | - Yueqi Chen
- Department of Biomedical Materials Science, Third Military Medical University (Army Medical University), Chongqing, China.,Department of Orthopedics, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, China
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Sukocheva OA, Furuya H, Ng ML, Friedemann M, Menschikowski M, Tarasov VV, Chubarev VN, Klochkov SG, Neganova ME, Mangoni AA, Aliev G, Bishayee A. Sphingosine kinase and sphingosine-1-phosphate receptor signaling pathway in inflammatory gastrointestinal disease and cancers: A novel therapeutic target. Pharmacol Ther 2020; 207:107464. [PMID: 31863815 DOI: 10.1016/j.pharmthera.2019.107464] [Citation(s) in RCA: 99] [Impact Index Per Article: 19.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Accepted: 12/10/2019] [Indexed: 02/07/2023]
Abstract
Inflammatory gastrointestinal (GI) diseases and malignancies are associated with growing morbidity and cancer-related mortality worldwide. GI tumor and inflammatory cells contain activated sphingolipid-metabolizing enzymes, including sphingosine kinase 1 (SphK1) and SphK2, that generate sphingosine-1-phosphate (S1P), a highly bioactive compound. Many inflammatory responses, including lymphocyte trafficking, are directed by circulatory S1P, present in high concentrations in both the plasma and the lymph of cancer patients. High fat and sugar diet, disbalanced intestinal flora, and obesity have recently been linked to activation of inflammation and SphK/S1P/S1P receptor (S1PR) signaling in various GI pathologies, including cancer. SphK1 overexpression and activation facilitate and enhance the development and progression of esophageal, gastric, and colon cancers. SphK/S1P axis, a mediator of inflammation in the tumor microenvironment, has recently been defined as a target for the treatment of GI disease states, including inflammatory bowel disease and colitis. Several SphK1 inhibitors and S1PR antagonists have been developed as novel anti-inflammatory and anticancer agents. In this review, we analyze the mechanisms of SphK/S1P signaling in GI tissues and critically appraise recent studies on the role of SphK/S1P/S1PR in inflammatory GI disorders and cancers. The potential role of SphK/S1PR inhibitors in the prevention and treatment of inflammation-mediated GI diseases, including GI cancer, is also evaluated.
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Affiliation(s)
- Olga A Sukocheva
- Discipline of Health Sciences, College of Nursing and Health Sciences, Flinders University, Bedford Park, South Australia 5042, Australia
| | - Hideki Furuya
- Department of Surgery, Samuel Oschin Cancer Center Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA
| | - Mei Li Ng
- Advanced Medical and Dental Institute, University Sains 13200 Kepala Batas, Pulau Pinang, Malaysia
| | - Markus Friedemann
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital `Carl Gustav Carus`, Technical University of Dresden, Dresden 01307, Germany
| | - Mario Menschikowski
- Institute of Clinical Chemistry and Laboratory Medicine, University Hospital `Carl Gustav Carus`, Technical University of Dresden, Dresden 01307, Germany
| | - Vadim V Tarasov
- Sechenov First Moscow State Medical University (Sechenov University), Moscow 119991, Russia
| | - Vladimir N Chubarev
- Sechenov First Moscow State Medical University (Sechenov University), Moscow 119991, Russia
| | - Sergey G Klochkov
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka 142432, Russia
| | - Margarita E Neganova
- Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka 142432, Russia
| | - Arduino A Mangoni
- Discipline of Clinical Pharmacology, College of Medicine and Public Health, Flinders University and Flinders Medical Centre, Bedford Park, South Australia 5042, Australia
| | - Gjumrakch Aliev
- Sechenov First Moscow State Medical University (Sechenov University), Moscow 119991, Russia; Institute of Physiologically Active Compounds, Russian Academy of Sciences, Chernogolovka 142432, Russia; GALLY International Research Institute, San Antonio, TX 78229, USA; Research Institute of Human Morphology, Moscow 117418, Russia
| | - Anupam Bishayee
- Lake Erie College of Osteopathic Medicine, Bradenton, FL 34211, USA.
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Sukocheva OA, Lukina E, McGowan E, Bishayee A. Sphingolipids as mediators of inflammation and novel therapeutic target in inflammatory bowel disease. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2020; 120:123-158. [PMID: 32085881 DOI: 10.1016/bs.apcsb.2019.11.003] [Citation(s) in RCA: 39] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
Morbidity of inflammatory gastrointestinal (GI) diseases continues to grow resulting in worsen quality of life and increased burden on public medical systems. Complex and heterogenous illnesses, inflammatory bowel diseases (IBDs) encompass several inflammation -associated pathologies including Crohn's disease and ulcerative colitis. IBD is often initiated by a complex interplay between host genetic and environmental factors, lifestyle and diet, and intestinal bacterial components. IBD inflammatory signature was linked to the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α) signaling pathway that is currently targeted by IBD therapies. Sphingolipid signaling was identified as one of the key mediators and regulators of pro-inflammatory conditions, and, specifically, TNF-α related signaling. All GI tissues and circulating immune/blood cells contain activated sphingolipid-metabolizing enzymes, including sphingosine kinases (SphK1 and SphK2) that generate sphingosine-1-phosphate (S1P), a bioactive lipid and ligand for five G-protein coupled membrane S1P receptors (S1PRs). Numerous normal and pathogenic inflammatory responses are mediated by SphK/S1P/S1PRs signaling axis including lymphocyte trafficking and activation of cytokine signaling machinery. SphK1/S1P/S1PRs axis has recently been defined as a target for the treatment of GI diseases including IBD/colitis. Several SphK1 inhibitors and S1PRs antagonists have been developed as novel anti-inflammatory agents. In this review, we discuss the mechanisms of SphK/S1P signaling in inflammation-linked GI disorders. The potential role of SphK/S1PRs inhibitors in the prevention and treatment of IBD/colitis is critically evaluated.
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Affiliation(s)
- Olga A Sukocheva
- Discipline of Health Sciences, College of Nursing and Health Sciences, Flinders University, Bedford Park, SA, Australia
| | - Elena Lukina
- Discipline of Health Sciences, College of Nursing and Health Sciences, Flinders University, Bedford Park, SA, Australia
| | - Eileen McGowan
- School of Life Sciences, Faculty of Science, University of Technology Sydney, Sydney, NSW, Australia
| | - Anupam Bishayee
- Lake Erie College of Osteopathic Medicine, Bradenton, FL, United States
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45
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Kim EY, Choi B, Kim JE, Park SO, Kim SM, Chang EJ. Interleukin-22 Mediates the Chemotactic Migration of Breast Cancer Cells and Macrophage Infiltration of the Bone Microenvironment by Potentiating S1P/SIPR Signaling. Cells 2020; 9:E131. [PMID: 31935914 PMCID: PMC7017200 DOI: 10.3390/cells9010131] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Revised: 12/30/2019] [Accepted: 01/03/2020] [Indexed: 12/16/2022] Open
Abstract
The interleukin-22 (IL-22) signaling pathway is well known to be involved in the progression of various cancer types but its role in bone metastatic breast cancer remains unclear. We demonstrate using human GEO profiling that bone metastatic breast cancer displays elevated interleukin-22 receptor 1 (IL-22R1) and sphingosine-1-phosphate receptor 1 (S1PR1) expression. Importantly, IL-22 stimuli promoted the expression of IL-22R1 and S1PR1 in aggressive MDA-MB-231 breast cancer cells. IL-22 treatment also increased sphingosine-1-phosphate production in mesenchymal stem cells (MSCs) and induced the sphingosine-1-phosphate (S1P)-mediated chemotactic migration of MDA-MB-231 cells. This effect was inhibited by an S1P antagonist. In addition to the S1PR1 axis, IL-22 stimulated the expression of matrix metalloproteinase-9 (MMP-9), thereby promoting breast cancer cell invasion. Moreover, IL-22 induced IL22R1 and S1PR1 expression in macrophages, myeloid cell, and MCP1 expression in MSCs to facilitate macrophage infiltration. Immunohistochemistry indicated that IL-22R1 and S1PR1 are overexpressed in invasive malignant breast cancers and that this correlates with the MMP-9 levels. Collectively, our present results indicate a potential role of IL-22 in driving the metastasis of breast cancers into the bone microenvironment through the IL22R1-S1PR1 axis.
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Affiliation(s)
- Eun-Young Kim
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (E.-Y.K.); (B.C.); (J.-E.K.); (S.-O.P.); (S.-M.K.)
- Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Bongkun Choi
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (E.-Y.K.); (B.C.); (J.-E.K.); (S.-O.P.); (S.-M.K.)
- Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Ji-Eun Kim
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (E.-Y.K.); (B.C.); (J.-E.K.); (S.-O.P.); (S.-M.K.)
- Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Si-On Park
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (E.-Y.K.); (B.C.); (J.-E.K.); (S.-O.P.); (S.-M.K.)
- Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
| | - Sang-Min Kim
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (E.-Y.K.); (B.C.); (J.-E.K.); (S.-O.P.); (S.-M.K.)
| | - Eun-Ju Chang
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea; (E.-Y.K.); (B.C.); (J.-E.K.); (S.-O.P.); (S.-M.K.)
- Stem Cell Immunomodulation Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
- Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul 05505, Korea
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46
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Wang X, Sun Y, Peng X, Naqvi SMAS, Yang Y, Zhang J, Chen M, Chen Y, Chen H, Yan H, Wei G, Hong P, Lu Y. The Tumorigenic Effect of Sphingosine Kinase 1 and Its Potential Therapeutic Target. Cancer Control 2020; 27:1073274820976664. [PMID: 33317322 PMCID: PMC8480355 DOI: 10.1177/1073274820976664] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 10/28/2020] [Accepted: 11/03/2020] [Indexed: 12/15/2022] Open
Abstract
Sphingosine kinase 1 (SPHK1) regulates cell proliferation and survival by converting sphingosine to the signaling mediator sphingosine 1-phosphate (S1P). SPHK1 is widely overexpressed in most cancers, promoting tumor progression and is associated with clinical prognosis. Numerous studies have explored SPHK1 as a promising target for cancer therapy. However, due to insufficient knowledge of SPHK1 oncogenic mechanisms, its inhibitors' therapeutic potential in preventing and treating cancer still needs further investigation. In this review, we summarized the metabolic balance regulated by the SPHK1/S1P signaling pathway and highlighted the oncogenic mechanisms of SPHK1 via the upregulation of autophagy, proliferation, and survival, migration, angiogenesis and inflammation, and inhibition of apoptosis. Drug candidates targeting SPHK1 were also discussed at the end. This review provides new insights into the oncogenic effect of SPHK1 and sheds light on the future direction for targeting SPHK1 as cancer therapy.
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Affiliation(s)
- Xianwang Wang
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, China
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, China
| | - Yong Sun
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, China
| | - Xiaochun Peng
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, China
| | - Syed Manzar Abbas Shah Naqvi
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, China
| | - Yue Yang
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, China
| | - Jing Zhang
- Department of Biochemistry and Molecular Biology, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, China
| | - Meiwen Chen
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, China
| | - Yuan Chen
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, China
| | - Hongyue Chen
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, China
| | - Huizi Yan
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, China
| | - Guangliang Wei
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei, China
| | - Peng Hong
- The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
| | - Yingying Lu
- The Seventh Affiliated Hospital, Sun Yat-sen University, Shenzhen, Guangdong, China
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47
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Gupta P, Mohammad T, Dahiya R, Roy S, Noman OMA, Alajmi MF, Hussain A, Hassan MI. Evaluation of binding and inhibition mechanism of dietary phytochemicals with sphingosine kinase 1: Towards targeted anticancer therapy. Sci Rep 2019; 9:18727. [PMID: 31822735 PMCID: PMC6904568 DOI: 10.1038/s41598-019-55199-3] [Citation(s) in RCA: 50] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2019] [Accepted: 11/08/2019] [Indexed: 12/13/2022] Open
Abstract
Sphingosine kinase 1 (SphK1) has recently gained attention as a potential drug target for its association with cancer and other inflammatory diseases. Here, we have investigated the binding affinity of dietary phytochemicals viz., ursolic acid, capsaicin, DL-α tocopherol acetate, quercetin, vanillin, citral, limonin and simvastatin with the SphK1. Docking studies revealed that all these compounds bind to the SphK1 with varying affinities. Fluorescence binding and isothermal titration calorimetric measurements suggested that quercetin and capsaicin bind to SphK1 with an excellent affinity, and significantly inhibits its activity with an admirable IC50 values. The binding mechanism of quercetin was assessed by docking and molecular dynamics simulation studies for 100 ns in detail. We found that quercetin acts as a lipid substrate competitive inhibitor, and it interacts with important residues of active-site pocket through hydrogen bonds and other non-covalent interactions. Quercetin forms a stable complex with SphK1 without inducing any significant conformational changes in the protein structure. In conclusion, we infer that quercetin and capsaicin provide a chemical scaffold to develop potent and selective inhibitors of SphK1 after required modifications for the clinical management of cancer.
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Affiliation(s)
- Preeti Gupta
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Taj Mohammad
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Rashmi Dahiya
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Sonam Roy
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India
| | - Omar Mohammed Ali Noman
- Department of Pharmacognosy College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Mohamed F Alajmi
- Department of Pharmacognosy College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia.
| | - Afzal Hussain
- Department of Pharmacognosy College of Pharmacy, King Saud University, Riyadh, 11451, Saudi Arabia
| | - Md Imtaiyaz Hassan
- Centre for Interdisciplinary Research in Basic Sciences, Jamia Millia Islamia, Jamia Nagar, New Delhi, 110025, India.
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48
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Anderson G. Breast cancer: Occluded role of mitochondria N-acetylserotonin/melatonin ratio in co-ordinating pathophysiology. Biochem Pharmacol 2019; 168:259-268. [PMID: 31310736 DOI: 10.1016/j.bcp.2019.07.014] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2019] [Accepted: 07/10/2019] [Indexed: 12/11/2022]
Abstract
A plethora of factors contribute to the biochemical underpinnings of breast cancer, in the absence of any clear, integrative framework. This article proposes that melatonergic pathway regulation within mitochondria provides an integrative framework for the wide array of data driving breast cancer pathophysiology. As melatonin is toxic to breast cancer cells, its production within mitochondria poses a significant challenge to breast cancer cell survival. Consequently, the diverse plasticity in breast cancer cells may arise from a requirement to decrease mitochondria melatonin synthesis. The aryl hydrocarbon receptor role in breast cancer pathophysiology may be mediated by an increase in cytochrome P450 (CYP)1b1 in mitochondria, leading to the backward conversion of melatonin to N-acetylserotonin (NAS). NAS has distinct effects to melatonin, including its activation of the tyrosine receptor kinase B (TrkB) receptor. TrkB activation significantly contributes to breast cancer cell survival and migration. However, the most important aspect of NAS induction by CYP1b1 in breast cancer cells is the prevention of melatonin effects in mitochondria. Many of the changes occurring in breast cancer cells arise from the need to regulate this pathway in mitochondria, allowing this to provide a framework that integrates a host of previously disparate data, including: microRNAs, estrogen, 14-3-3 proteins, sirtuins, glycolysis, oxidative phosphorylation, indoleamine 2,3-dioxygenase and the kynurenine pathways. It is also proposed that this framework provides a pathoetiological model incorporating the early developmental regulation of the gut microbiome that integrates breast cancer risk factors, including obesity. This has significant treatment, prevention and research implications.
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Affiliation(s)
- George Anderson
- CRC Scotland & London, Eccleston Square, London SW1V 1PH, UK.
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49
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Singh S, Chakrabarti R. Consequences of EMT-Driven Changes in the Immune Microenvironment of Breast Cancer and Therapeutic Response of Cancer Cells. J Clin Med 2019; 8:jcm8050642. [PMID: 31075939 PMCID: PMC6572359 DOI: 10.3390/jcm8050642] [Citation(s) in RCA: 45] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 04/30/2019] [Accepted: 05/04/2019] [Indexed: 02/06/2023] Open
Abstract
Epithelial-to-mesenchymal transition (EMT) is a process through which epithelial cells lose their epithelial characteristics and cell–cell contact, thus increasing their invasive potential. In addition to its well-known roles in embryonic development, wound healing, and regeneration, EMT plays an important role in tumor progression and metastatic invasion. In breast cancer, EMT both increases the migratory capacity and invasive potential of tumor cells, and initiates protumorigenic alterations in the tumor microenvironment (TME). In particular, recent evidence has linked increased expression of EMT markers such as TWIST1 and MMPs in breast tumors with increased immune infiltration in the TME. These immune cells then provide cues that promote immune evasion by tumor cells, which is associated with enhanced tumor progression and metastasis. In the current review, we will summarize the current knowledge of the role of EMT in the biology of different subtypes of breast cancer. We will further explore the correlation between genetic switches leading to EMT and EMT-induced alterations within the TME that drive tumor growth and metastasis, as well as their possible effect on therapeutic response in breast cancer.
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Affiliation(s)
- Snahlata Singh
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
| | - Rumela Chakrabarti
- Department of Biomedical Sciences, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
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50
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Talmont F, Moulédous L, Baranger M, Gomez-Brouchet A, Zajac JM, Deffaud C, Cuvillier O, Hatzoglou A. Development and characterization of sphingosine 1-phosphate receptor 1 monoclonal antibody suitable for cell imaging and biochemical studies of endogenous receptors. PLoS One 2019; 14:e0213203. [PMID: 30845158 PMCID: PMC6405204 DOI: 10.1371/journal.pone.0213203] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2018] [Accepted: 02/15/2019] [Indexed: 11/18/2022] Open
Abstract
Although sphingosine-1-phosphate receptor 1 (S1P1) has been shown to trigger several S1P targeted functions such as immune cell trafficking, cell proliferation, migration, or angiogenesis, tools that allow the accurate detection of endogenous S1P1 localization and trafficking remain to be obtained and validated. In this study, we developed and characterized a novel monoclonal S1P1 antibody. Mice were immunized with S1P1 produced in the yeast Pichia pastoris and nine hybridoma clones producing monoclonal antibodies were created. Using different technical approaches including Western blot, immunoprecipitation and immunocytochemistry, we show that a selected clone, hereinafter referred to as 2B9, recognizes human and mouse S1P1 in various cell lineages. The interaction between 2B9 and S1P1 is specific over receptor subtypes, as the antibody does not binds to S1P2 or S1P5 receptors. Using cell-imaging methods, we demonstrate that 2B9 binds to an epitope located at the intracellular domain of S1P1; reveals cytosolic and membrane localization of the endogenous S1P1; and receptor internalization upon S1P or FTY720-P stimulation. Finally, loss of 2B9 signal upon knockdown of endogenous S1P1 by specific small interference RNAs further confirms its specificity. 2B9 was also able to detect S1P1 in human kidney and spinal cord tissue by immunohistochemistry. Altogether, our results suggest that 2B9 could be a useful tool to detect, quantify or localize low amounts of endogenous S1P1 in various physiological and pathological processes.
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Affiliation(s)
- Franck Talmont
- Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Lionel Moulédous
- Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France
| | | | - Anne Gomez-Brouchet
- Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France.,Service d'anatomie et cytologie pathologiques, IUCT Oncopole, Toulouse, France
| | - Jean-Marie Zajac
- Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France
| | | | - Olivier Cuvillier
- Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France
| | - Anastassia Hatzoglou
- Institut de Pharmacologie et de Biologie Structurale, Université de Toulouse, CNRS, UPS, Toulouse, France
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