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See LC, Wu CY, Tsai CY, Lee CC, Chen JJ, Jenq CC, Chen CY, Chen YC, Yen CL, Yang HY. PPAR-γ agonist pioglitazone and the risks of malignancy among type2 diabetes mellitus patients. Acta Diabetol 2025; 62:531-542. [PMID: 39347851 DOI: 10.1007/s00592-024-02378-y] [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: 06/01/2024] [Accepted: 09/13/2024] [Indexed: 10/01/2024]
Abstract
AIMS PPAR-gamma shows promise in inhibiting malignancy cell progression. However, pioglitazone, the sole current PPAR-gamma agonist, was reported to have risks of bladder cancer in previous clinical researches. This study is aimed to assess the influence of pioglitazone on the development of tumors. METHODS By using Taiwan's National Health Insurance Research Database, this nested case-control study identified incident type2 diabetes initiating metformin treatment between 2000 and 2014, and then categorized into two groups based on whether they developed malignancies after enrollment or not. The index date was defined as the date of malignancy diagnosis in the cancer group or a matched date in the non-cancer group. We analyzed the exposure to pioglitazone preceding the index date. RESULTS 47,931 patients in the cancer group and 47,931 patients in the matched non-cancer group were included. The non-cancer group exhibited a significantly higher rate of pioglitazone prescription before the index date for overall malignancies (odds ratios for pioglitazone use were 0.91, 0.92, 0.94, and 0.93 in the first, second, third, and fourth years before the index date). For breast cancer and prostate cancer, pioglitazone was frequently prescribed in the non-cancer group, whereas for pancreatic cancer, pioglitazone use was more common in the cancer group. CONCLUSIONS PPAR-gamma agonists may be associated with reduced risks of overall malignancies, particularly for breast and prostate cancers. However, it may be linked to an elevated risk of pancreatic cancer.
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Affiliation(s)
- Lai-Chu See
- Department of Public Health, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Biostatistics Core Laboratory, Molecular Medicine Research Center, Chang Gung University, Taoyuan, Taiwan
| | - Chao-Yi Wu
- Division of Allergy, Asthma, and Rheumatology, Department of Pediatrics, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan, Taiwan
- Division of Rheumatology, Allergy and Immunology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
| | - Chung-Ying Tsai
- Nephrology Department, Linkou Medical Center, College of Medicine, Kidney Research Institute Chang Gung Memorial Hospital Chang Gung University, No.5, Fuxing Street, Guishan District, Taoyuan, 33305, Taiwan
| | - Cheng-Chia Lee
- Nephrology Department, Linkou Medical Center, College of Medicine, Kidney Research Institute Chang Gung Memorial Hospital Chang Gung University, No.5, Fuxing Street, Guishan District, Taoyuan, 33305, Taiwan
| | - Jia-Jin Chen
- Nephrology Department, Linkou Medical Center, College of Medicine, Kidney Research Institute Chang Gung Memorial Hospital Chang Gung University, No.5, Fuxing Street, Guishan District, Taoyuan, 33305, Taiwan
| | - Chang-Chyi Jenq
- Nephrology Department, Linkou Medical Center, College of Medicine, Kidney Research Institute Chang Gung Memorial Hospital Chang Gung University, No.5, Fuxing Street, Guishan District, Taoyuan, 33305, Taiwan
| | - Chao-Yu Chen
- Nephrology Department, Linkou Medical Center, College of Medicine, Kidney Research Institute Chang Gung Memorial Hospital Chang Gung University, No.5, Fuxing Street, Guishan District, Taoyuan, 33305, Taiwan
| | - Yung-Chang Chen
- Nephrology Department, Linkou Medical Center, College of Medicine, Kidney Research Institute Chang Gung Memorial Hospital Chang Gung University, No.5, Fuxing Street, Guishan District, Taoyuan, 33305, Taiwan
| | - Chieh-Li Yen
- Nephrology Department, Linkou Medical Center, College of Medicine, Kidney Research Institute Chang Gung Memorial Hospital Chang Gung University, No.5, Fuxing Street, Guishan District, Taoyuan, 33305, Taiwan.
| | - Huang-Yu Yang
- Nephrology Department, Linkou Medical Center, College of Medicine, Kidney Research Institute Chang Gung Memorial Hospital Chang Gung University, No.5, Fuxing Street, Guishan District, Taoyuan, 33305, Taiwan.
- Department of Health Policy and Management, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, U.S.A..
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Xu L, Xiong L, Chen Y, Chen J, Liu X, Xu Y, Shen Y, Wang S, Yu S, Xu X. IGFALS suppresses hepatocellular carcinoma progression by stabilizing PPAR-γ. Int Immunopharmacol 2024; 143:113414. [PMID: 39471694 DOI: 10.1016/j.intimp.2024.113414] [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: 07/27/2024] [Revised: 09/22/2024] [Accepted: 10/13/2024] [Indexed: 11/01/2024]
Abstract
IGFALS forms stable ternary complexes with insulin-like growth factors (IGF1 and IGF2) and IGF-binding proteins (IGFBP3 and IGFBP5), which prolong the half-lives of IGFs. Through immunohistochemical analysis of 90 pairs of clinical samples and bioinformatics analysis, we observed downregulation of IGFALS in hepatocellular carcinoma tissues, which was associated with poor patient prognosis. This prompted us to explore the specific molecular mechanism of action of IGFALS in the inhibition of hepatocellular carcinoma (HCC), which could be a potential new target for the treatment of HCC. In vitro experiments demonstrated that IGFALS inhibits the proliferation, invasion, and migration of hepatocellular carcinoma cells and suppresses epithelial-mesenchymal transition. Gene Set Enrichment Analysis (GSEA) revealed a positive correlation between IGFALS and the activation of the PPAR pathway. Western blotting, immunofluorescence colocalization, and co-immunoprecipitation assays confirmed that IGFALS binds to PPAR-γ and stabilizes it through deubiquitination. Inhibition of PPAR-γ reversed the anticancer effects of IGFALS. Furthermore, we showed that IGFALS/PPAR-γ upregulates the expression of HMGCS2. The tumor xenograft model supported our findings. Mass spectrometry analysis and co-immunoprecipitation assays indicated that IGFALS promotes the binding of PPAR-γ with USP9X, a deubiquitinating enzyme, thereby facilitating the deubiquitination of PPAR-γ. In conclusion, our findings demonstrate that IGFALS can suppress hepatocellular carcinoma via the PPAR-γ/HMGCS2 pathway.
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Affiliation(s)
- Le Xu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Lin Xiong
- Department of pathology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Yukai Chen
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Jiayu Chen
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Xiaohong Liu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Yangtao Xu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Yang Shen
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Siyu Wang
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Shuhong Yu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Ximing Xu
- Cancer Center, Renmin Hospital of Wuhan University, Wuhan, Hubei, China.
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Misceo D, Mocciaro G, D'Amore S, Vacca M. Diverting hepatic lipid fluxes with lifestyles revision and pharmacological interventions as a strategy to tackle steatotic liver disease (SLD) and hepatocellular carcinoma (HCC). Nutr Metab (Lond) 2024; 21:112. [PMID: 39716321 DOI: 10.1186/s12986-024-00871-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 11/13/2024] [Indexed: 12/25/2024] Open
Abstract
Steatotic liver disease (SLD) and Hepatocellular Carcinoma (HCC) are characterised by a substantial rewiring of lipid fluxes caused by systemic metabolic unbalances and/or disrupted intracellular metabolic pathways. SLD is a direct consequence of the interaction between genetic predisposition and a chronic positive energy balance affecting whole-body energy homeostasis and the function of metabolically-competent organs. In this review, we discuss how the impairment of the cross-talk between peripheral organs and the liver stalls glucose and lipid metabolism, leading to unbalances in hepatic lipid fluxes that promote hepatic fat accumulation. We also describe how prolonged metabolic stress builds up toxic lipid species in the liver, and how lipotoxicity and metabolic disturbances drive disease progression by promoting a chronic activation of wound healing, leading to fibrosis and HCC. Last, we provide a critical overview of current state of the art (pre-clinical and clinical evidence) regarding mechanisms of action and therapeutic efficacy of candidate SLD treatment options, and their potential to interfere with SLD/HCC pathophysiology by diverting lipids away from the liver therefore improving metabolic health.
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Affiliation(s)
- Davide Misceo
- Department of Interdisciplinary Medicine, Clinica Medica "C. Frugoni", "Aldo Moro" University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy
| | - Gabriele Mocciaro
- Roger Williams Institute of Liver Studies, Foundation for Liver Research, London, SE5 9NT, UK
| | - Simona D'Amore
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), Clinica Medica "G. Baccelli", "Aldo Moro" University of Bari, 70124, Bari, Italy.
| | - Michele Vacca
- Department of Interdisciplinary Medicine, Clinica Medica "C. Frugoni", "Aldo Moro" University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy.
- Roger Williams Institute of Liver Studies, Foundation for Liver Research, London, SE5 9NT, UK.
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4
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Pratama AM, Sharma M, Naidu S, Bömmel H, Prabhuswamimath SC, Madhusudhan T, Wihadmadyatami H, Bachhuka A, Karnati S. Peroxisomes and PPARs: Emerging role as master regulators of cancer metabolism. Mol Metab 2024; 90:102044. [PMID: 39368612 PMCID: PMC11550351 DOI: 10.1016/j.molmet.2024.102044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Revised: 09/16/2024] [Accepted: 09/30/2024] [Indexed: 10/07/2024] Open
Abstract
Cancer is a disease characterized by the acquisition of a multitude of unique traits. It has long been understood that cancer cells divert significantly from normal cell metabolism. The most obvious of metabolic changes is that cancer cells strongly rely on glucose conversion by aerobic glycolysis. In addition, they also regularly develop mechanisms to use lipids and fatty acids for their energy needs. Peroxisomes lie central to these adaptive changes of lipid metabolism. Peroxisomes are metabolic organelles that take part in over 50 enzymatic reactions crucial for cellular functioning. Thus, they are essential for an effective and comprehensive use of lipids' energy supplied to cells. Cancer cells display a substantial increase in the biogenesis of peroxisomes and an increased expression of proteins necessary for the enzymatic functions provided by peroxisomes. Moreover, the enzymatic conversion of FAs in peroxisomes is a significant source of reactive oxygen and nitrogen species (ROS/RNS) that strongly impact cancer malignancy. Important regulators in peroxisomal FA oxidation and ROS/RNS generation are the transcription factors of the peroxisome proliferator-activated receptor (PPAR) family. This review describes the metabolic changes in tumorigenesis and cancer progression influenced by peroxisomes. We will highlight the ambivalent role that peroxisomes and PPARs play in the different stages of tumor development and summarize our current understanding of how to capitalize on the comprehension of peroxisomal biology for cancer treatment.
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Affiliation(s)
- Anggi Muhtar Pratama
- University of Würzburg, Institute of Anatomy and Cell Biology, Würzburg, Germany
| | - Mansi Sharma
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, India
| | - Srivatsava Naidu
- Department of Biomedical Engineering, Indian Institute of Technology Ropar, India
| | - Heike Bömmel
- University of Würzburg, Institute of Anatomy and Cell Biology, Würzburg, Germany
| | - Samudyata C Prabhuswamimath
- Department of Biotechnology and Bioinformatics, School of Life Sciences, JSS Academy of Higher Education and Research, Mysuru, 570 015, Karnataka, India
| | - Thati Madhusudhan
- Center for Thrombosis and Hemostasis, University Medical Center Mainz, Langenbeckstr. 1, 55131 Mainz, Germany
| | - Hevi Wihadmadyatami
- Department of Anatomy, Faculty of Veterinary Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Akash Bachhuka
- Institute of Chemical Research of Catalonia (ICIQ), Av. Països Catalans 16, 43007 Tarragona, Spain.
| | - Srikanth Karnati
- University of Würzburg, Institute of Anatomy and Cell Biology, Würzburg, Germany.
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5
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Xie R, Luo Y, Bao B, Wu X, Guo J, Wang J, Qu X, Che X, Zheng C. The Role of Fatty Acid Metabolism, the Related Potential Biomarkers, and Targeted Therapeutic Strategies in Gastrointestinal Cancers. Drug Dev Res 2024; 85:e70014. [PMID: 39527665 DOI: 10.1002/ddr.70014] [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: 05/17/2024] [Revised: 10/12/2024] [Accepted: 10/13/2024] [Indexed: 11/16/2024]
Abstract
Gastrointestinal cancer has emerged as a significant global health concern due to its high incidence and mortality, limited effectiveness of early detection, suboptimal treatment outcomes, and poor prognosis. Metabolic reprogramming is a prominent feature of cancer, and fatty acid metabolism assumes a pivotal role in bridging glucose metabolism and lipid metabolism. Fatty acids play important roles in cellular structural composition, energy supply, signal transduction, and other lipid-related processes. Changes in the levels of fatty acid metabolite may indicate the malignant transformation of gastrointestinal cells, which have an impact on the prognosis of patients and can be used as a marker to monitor the efficacy of anticancer therapy. Therefore, targeting key enzymes involved in fatty acid metabolism, either as monotherapy or in combination with other agents, is a promising strategy for anticancer treatment. This article reviews the potential mechanisms of fatty acid metabolism disorders in the occurrence and development of gastrointestinal tumors, and summarizes the related potential biomarkers and anticancer strategies.
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Affiliation(s)
- Ruixi Xie
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Ying Luo
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Bowen Bao
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xinshu Wu
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jia Guo
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Jin Wang
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xiujuan Qu
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Xiaofang Che
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
| | - Chunlei Zheng
- Department of Medical Oncology, Provincial Key Laboratory of Anticancer Drugs and Biotherapy of Liaoning Province, Clinical Cancer Research Center of Shenyang, The First Hospital of China Medical University, Shenyang, Liaoning, China
- Department of Oncology, Shanghai Electric Power Hospital, Shanghai, China
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6
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Takahashi S. Signaling effect, combinations, and clinical applications of triciribine. J Chemother 2024:1-9. [PMID: 39275964 DOI: 10.1080/1120009x.2024.2403050] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 08/29/2024] [Accepted: 09/06/2024] [Indexed: 09/16/2024]
Abstract
Triciribine (TCN) is a tricyclic nucleoside. Its synthesis was first described in 1971. Subsequent studies have indicated that TCN plays a role in inhibiting DNA synthesis and was revealed to possess a higher selectivity for Akt. Although a single dose of TCN demonstrated limited activity in solid tumors at the clinical level, combinations of TCN with various agents, such as specific inhibitors, tyrosine kinase inhibitor dasatinib, ErbB inhibitor tipifarnib, IGF1-R inhibitor NVP-AEW541, mTORC1 inhibitor RAD-001, TNF-related apoptosis-inducing ligand, PPARγ agonist, 1,25(OH)2D3, gemcitabine, and paclitaxel, have been reported to be efficient against various malignancies such as pancreatic, breast, prostate cancer, insulinoma, gut neuroendocrine tumor, and hepatocellular carcinoma at the preclinical level. Other than malignancies, through Akt inhibition activity, TCN has also been demonstrated potential for treating lung injuries, including those encountered in COVID-19 infections.
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Affiliation(s)
- Shinichiro Takahashi
- Division of Laboratory Medicine, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, Sendai, Japan
- Institute of Molecular Biomembrane and Glycobiology, Tohoku Medical and Pharmaceutical University, Sendai, Miyagi, Japan
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7
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Zhao Y, Tan H, Zhang X, Zhu J. Roles of peroxisome proliferator-activated receptors in hepatocellular carcinoma. J Cell Mol Med 2024; 28:e18042. [PMID: 37987033 PMCID: PMC10902579 DOI: 10.1111/jcmm.18042] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2023] [Revised: 10/18/2023] [Accepted: 10/25/2023] [Indexed: 11/22/2023] Open
Abstract
Hepatocellular carcinoma (HCC), the main pathological type of liver cancer, is linked to risk factors such as viral hepatitis, alcohol intake and non-alcoholic fatty liver disease (NAFLD). Recent advances have greatly improved our understanding that NAFLD is playing a major risk factor for HCC. Peroxisome proliferator-activated receptors (PPARs) are a class of transcription factors divided into three subtypes: PPARα (PPARA), PPARδ/β (PPARD) and PPARγ (PPARG). As important nuclear receptors, PPARs are involved in many physiological processes, and PPARs can improve NAFLD by regulating lipid metabolism, accelerating fatty acid oxidation and inhibiting inflammation. In recent years, some studies have shown that PPARs can participate in the occurrence and development of HCC by regulating metabolic pathways. In addition, PPAR modulators have been reported to inhibit the proliferation and metastasis of HCC cells and can enhance the curative effect of conventional treatments. This article reviews the role of PPARs in the occurrence and development of HCC, as well as its value in the diagnosis, treatment and prognosis of HCC, in order to provide directions for future research.
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Affiliation(s)
- Yaqin Zhao
- Department of Abdominal Oncology, Cancer Center, West China HospitalSichuan UniversityChengduChina
| | - Huabing Tan
- Department of Infectious Diseases, Liver Disease Laboratory, Renmin HospitalHubei University of MedicineShiyanHubeiChina
| | - Xiaoyu Zhang
- Division of Gastrointestinal Surgery, Department of General SurgeryThe Affiliated Huai'an Hospital of Xuzhou Medical UniversityHuai'anChina
| | - Jing Zhu
- Nanjing Drum Tower HospitalNanjingChina
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8
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Sarkar S, Das AK, Bhattacharya S, Gachhui R, Sil PC. Isorhamnetin exerts anti-tumor activity in DEN + CCl 4-induced HCC mice. Med Oncol 2023; 40:188. [PMID: 37226027 DOI: 10.1007/s12032-023-02050-5] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2023] [Accepted: 05/06/2023] [Indexed: 05/26/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is the most prevalent type of liver cancer and the main cause of cancer death globally. The use of medicinal herbs as chemotherapeutic agents in cancer treatment is receiving attention as they possess no or minimum side effects. Isorhamnetin (IRN), a flavonoid, has been under attention for its anti-inflammatory and anti-proliferative properties in a number of cancers, including colorectal, skin, and lung cancers. However, the in vivo mechanism of isorhamnetin to suppress liver cancer has yet to be explored. METHODS AND RESULT HCC was induced by N-diethylnitrosamine (DEN) and carbon tetrachloride (CCL4) in Swiss albino mice. Isorhamnetin (100 mg/kg body weight) was given to examine its anti-tumor properties in HCC mice model. Histological analysis and liver function assays were performed to assess changes in liver anatomy. Probable molecular pathways were explored using immunoblot, qPCR, ELISA, and immunohistochemistry techniques. Isorhamnetin inhibited various pro-inflammatory cytokines to suppress cancer-inducing inflammation. Additionally, it regulated Akt and MAPKs to suppress Nrf2 signaling. Isorhamnetin activated PPAR-γ and autophagy while suppressing cell cycle progression in DEN + CCl4-administered mice. Additionally, isorhamnetin regulated various signaling pathways to suppress cell proliferation, metabolism, and epithelial-mesenchymal transition in HCC. CONCLUSION Regulating diverse cellular signaling pathways makes isorhamnetin a better anti-cancer chemotherapeutic candidate in HCC. Importantly, the anti-TNF-α properties of isorhamnetin could prove it a valuable therapeutic agent in sorafenib-resistant HCC patients. Additionally, anti-TGF-β properties of isorhamnetin could be utilized to reduce the EMT-inducing side effects of doxorubicin.
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Affiliation(s)
- Sayanta Sarkar
- Department of Life Sciences & Biotechnology, Jadavpur University, 188, Raja SC Mullick Road, Kolkata, 700032, India
| | - Abhishek Kumar Das
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, West Bengal, 700054, India
| | - Semantee Bhattacharya
- Indian Association for the Cultivation of Science, 2A & 2B, Raja Subodh Chandra Mallick Rd, Jadavpur, Kolkata, West Bengal, 700032, India
| | - Ratan Gachhui
- Department of Life Sciences & Biotechnology, Jadavpur University, 188, Raja SC Mullick Road, Kolkata, 700032, India
| | - Parames C Sil
- Division of Molecular Medicine, Bose Institute, P-1/12, CIT Scheme VII M, Kolkata, West Bengal, 700054, India.
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9
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Sun J, Yu L, Qu X, Huang T. The role of peroxisome proliferator-activated receptors in the tumor microenvironment, tumor cell metabolism, and anticancer therapy. Front Pharmacol 2023; 14:1184794. [PMID: 37251321 PMCID: PMC10213337 DOI: 10.3389/fphar.2023.1184794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2023] [Accepted: 05/05/2023] [Indexed: 05/31/2023] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) have been extensively studied for over 3 decades and consist of three isotypes, including PPARα, γ, and β/δ, that were originally considered key metabolic regulators controlling energy homeostasis in the body. Cancer has become a leading cause of human mortality worldwide, and the role of peroxisome proliferator-activated receptors in cancer is increasingly being investigated, especially the deep molecular mechanisms and effective cancer therapies. Peroxisome proliferator-activated receptors are an important class of lipid sensors and are involved in the regulation of multiple metabolic pathways and cell fate. They can regulate cancer progression in different tissues by activating endogenous or synthetic compounds. This review emphasizes the significance and knowledge of peroxisome proliferator-activated receptors in the tumor microenvironment, tumor cell metabolism, and anti-cancer treatment by summarizing recent research on peroxisome proliferator-activated receptors. In general, peroxisome proliferator-activated receptors either promote or suppress cancer in different types of tumor microenvironments. The emergence of this difference depends on various factors, including peroxisome proliferator-activated receptor type, cancer type, and tumor stage. Simultaneously, the effect of anti-cancer therapy based on drug-targeted PPARs differs or even opposes among the three peroxisome proliferator-activated receptor homotypes and different cancer types. Therefore, the current status and challenges of the use of peroxisome proliferator-activated receptors agonists and antagonists in cancer treatment are further explored in this review.
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Affiliation(s)
- Jiaao Sun
- Department of Urology, First Affiliated Hospital, Dalian Medical University, Dalian, China
| | - Liyan Yu
- Department of Respiratory and Critical Care Medicine, First Affiliated Hospital, Dalian Medical University, Dalian, Liaoning, China
| | - Xueling Qu
- Dalian Women and Children’s Medical Center(Group), Dalian, Liaoning, China
| | - Tao Huang
- Department of Urology, First Affiliated Hospital, Dalian Medical University, Dalian, China
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10
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Ebrahimi N, Far NP, Fakhr SS, Faghihkhorasani F, Miraghel SA, Chaleshtori SR, Rezaei-Tazangi F, Beiranvand S, Baziyar P, Manavi MS, Zarrabi A, Nabavi N, Ren J, Aref AR. The endocannabinoid system, a new gatekeeper in the pharmacology of human hepatocellular carcinoma. ENVIRONMENTAL RESEARCH 2023; 228:115914. [PMID: 37062475 DOI: 10.1016/j.envres.2023.115914] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/03/2023] [Revised: 04/01/2023] [Accepted: 04/13/2023] [Indexed: 05/06/2023]
Abstract
Despite numerous prevention methodologies and treatment options, hepatocellular carcinoma (HCC) still remains as the third leading life-threatening cancer. It is thus pertinent to develop new treatment modality to fight this devastating carcinoma. Ample recent studies have shown the anti-inflammatory and antitumor roles of the endocannabinoid system in various forms of cancers. Preclinical studies have also confirmed that cannabinoid therapy can be an optimal regimen for cancer treatments. The endocannabinoid system is involved in many cancer-related processes, including induction of endoplasmic reticulum (ER) stress-dependent apoptosis, autophagy, PITRK and ERK signaling pathways, cell invasion, epithelial-mesenchymal transition (EMT), and cancer stem cell (CSC) phenotypes. Moreover, changes in signaling transduction of the endocannabinoid system can be a potential diagnostic and prognostic biomarker for HCC. Due to its pivotal role in lipid metabolism, the endocannabinoid system affects metabolic reprogramming as well as lipid content of exosomes. In addition, due to the importance of non-coding RNAs (ncRNAs), several studies have examined the relationship between microRNAs and the endocannabinoid system in HCC. However, HCC is a pathological condition with high heterogeneity, and therefore using the endocannabinoid system for treatment has faced many controversies. While some studies favored a role of the endocannabinoid system in carcinogenesis and tumor induction, others exhibited the anticancer potential of endocannabinoids in HCC. In this review, specific studies delineating the relationship between endocannabinoids and HCC are examined. Based on collected findings, detailed studies of the molecular mechanism of endocannabinoids as well as preclinical studies for investigating therapeutic or carcinogenic impacts in HCC cancer are strongly suggested.
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Affiliation(s)
- Nasim Ebrahimi
- Genetics Division, Department of Cell and Molecular Biology and Microbiology, Faculty of Science and Technology, University of Isfahan, Iran
| | - Nazanin Pazhouhesh Far
- Department of Microbiology,Faculty of Advanced Science and Technology, Tehran Medical Science, Islamic Azad University, Tehran, Iran
| | - Siavash Seifollahy Fakhr
- Division of Biotechnology, Faculty of Applied Ecology, Agricultural Sciences and Biotechnology, Campus, Hamar, Norway
| | | | - Seyed Ali Miraghel
- Nocivelli Institute for Molecular Medicine, Department of Molecular and Translational Medicine, University of Brescia, Italy
| | | | - Fatemeh Rezaei-Tazangi
- Department of Anatomy, School of Medicine, Fasa University of Medical Sciences, Fasa, Iran
| | - Sheida Beiranvand
- Department of Biotechnology, School of Basic Sciences, Shahrekord Branch, Islamic Azad University, Shahrekord, Iran
| | - Payam Baziyar
- Department of Molecular and Cell Biology, Faculty of Basic Science, Uinversity of Mazandaran, Babolsar, Iran
| | | | - Ali Zarrabi
- Department of Biomedical Engineering, Faculty of Engineering and Natural Sciences, Istinye University, Istanbul, 34396, Turkey
| | - Noushin Nabavi
- Department of Urological Sciences and Vancouver Prostate Centre, University of British Columbia, Vancouver, BC, V6H3Z6, Canada
| | - Jun Ren
- Department of Cardiology, Zhongshan Hospital Fudan University, Shanghai, 200032, China; Department of Laboratory Medicine and Pathology, University of Washington, WA, 98195, USA
| | - Amir Reza Aref
- Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02115, USA; Xsphera Biosciences, Translational Medicine Group, 6 Tide Street, Boston, MA, 02210, USA.
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Abou-Fadel J, Reid V, Le A, Croft J, Zhang J. Key Members of the CmPn as Biomarkers Distinguish Histological and Immune Subtypes of Hepatic Cancers. Diagnostics (Basel) 2023; 13:diagnostics13061012. [PMID: 36980321 PMCID: PMC10047786 DOI: 10.3390/diagnostics13061012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2023] [Revised: 02/23/2023] [Accepted: 03/05/2023] [Indexed: 03/11/2023] Open
Abstract
Liver cancer, comprising hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), is a leading cause of cancer-related deaths worldwide. The liver is a primary metabolic organ for progesterone (PRG) and PRG exerts its effects through classic nuclear PRG receptors (nPRs) and non-classic membrane PRG receptors (mPRs) or a combination of both. Previous studies have shown that the CCM signaling complex (CSC) couples both nPRs and mPRs to form the CmPn (CSC-mPR-PRG-nPR) signaling network, which is involved in multiple cellular signaling pathways, including tumorigenesis of various cancers. Despite advances in treatment, 5-year survival rates for liver cancer patients remain low, largely due to the chemoresistant nature of HCCs. The lack of sensitive and specific biomarkers for liver cancer diagnosis and prognosis emphasizes the need for identifying new potential biomarkers. We propose the potential use of CmPn members’ expression data as prognostic biomarkers or biomarker signatures for the major types of hepatic cancer, including HCCs and CCAs, as well as rare subtypes such as undifferentiated pleomorphic sarcoma (UPS) and hepatic angiosarcoma (HAS). In this study, we investigated the CmPn network through RNAseq data and immunofluorescence techniques to measure alterations to key cancer pathways during liver tumorigenesis. Our findings reveal significant differential expression of multiple CmPn members, including CCM1, PAQR7, PGRMC1, and nPRs, in both HCCs and CCAs, highlighting the crucial roles of mPRs, nPRs, and CSC signaling during liver tumorigenesis. These key members of the CmPn network may serve as potential biomarkers for the diagnosis and prognosis of liver cancer subtypes, including rare subtypes.
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Affiliation(s)
| | | | | | | | - Jun Zhang
- Correspondence: ; Tel.: +1-(915)-215-4197
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12
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Peroxisome proliferator-activated receptor ɣ agonist mediated inhibition of heparanase expression reduces proteinuria. EBioMedicine 2023; 90:104506. [PMID: 36889064 PMCID: PMC10043778 DOI: 10.1016/j.ebiom.2023.104506] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2022] [Revised: 02/16/2023] [Accepted: 02/16/2023] [Indexed: 03/08/2023] Open
Abstract
BACKGROUND Proteinuria is associated with many glomerular diseases and a risk factor for the progression to renal failure. We previously showed that heparanase (HPSE) is essential for the development of proteinuria, whereas peroxisome proliferator-activated receptor ɣ (PPARɣ) agonists can ameliorate proteinuria. Since a recent study showed that PPARɣ regulates HPSE expression in liver cancer cells, we hypothesized that PPARɣ agonists exert their reno-protective effect by inhibiting glomerular HPSE expression. METHODS Regulation of HPSE by PPARɣ was assessed in the adriamycin nephropathy rat model, and cultured glomerular endothelial cells and podocytes. Analyses included immunofluorescence staining, real-time PCR, heparanase activity assay and transendothelial albumin passage assay. Direct binding of PPARɣ to the HPSE promoter was evaluated by the luciferase reporter assay and chromatin immunoprecipitation assay. Furthermore, HPSE activity was assessed in 38 type 2 diabetes mellitus (T2DM) patients before and after 16/24 weeks treatment with the PPARɣ agonist pioglitazone. FINDINGS Adriamycin-exposed rats developed proteinuria, an increased cortical HPSE and decreased heparan sulfate (HS) expression, which was ameliorated by treatment with pioglitazone. In line, the PPARɣ antagonist GW9662 increased cortical HPSE and decreased HS expression, accompanied with proteinuria in healthy rats, as previously shown. In vitro, GW9662 induced HPSE expression in both endothelial cells and podocytes, and increased transendothelial albumin passage in a HPSE-dependent manner. Pioglitazone normalized HPSE expression in adriamycin-injured human endothelial cells and mouse podocytes, and adriamycin-induced transendothelial albumin passage was reduced as well. Importantly, we demonstrated a regulatory effect of PPARɣ on HPSE promoter activity and direct PPARy binding to the HPSE promoter region. Plasma HPSE activity of T2DM patients treated with pioglitazone for 16/24 weeks was related to their hemoglobin A1c and showed a moderate, near significant correlation with plasma creatinine levels. INTERPRETATION PPARɣ-mediated regulation of HPSE expression appears an additional mechanism explaining the anti-proteinuric and renoprotective effects of thiazolidinediones in clinical practice. FUNDING This study was financially supported by the Dutch Kidney Foundation, by grants 15OI36, 13OKS023 and 15OP13. Consortium grant LSHM16058-SGF (GLYCOTREAT; a collaboration project financed by the PPP allowance made available by Top Sector Life Sciences & Health to the Dutch Kidney Foundation to stimulate public-private partnerships).
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Senn L, Costa AM, Avallone R, Socała K, Wlaź P, Biagini G. Is the peroxisome proliferator-activated receptor gamma a putative target for epilepsy treatment? Current evidence and future perspectives. Pharmacol Ther 2023; 241:108316. [PMID: 36436690 DOI: 10.1016/j.pharmthera.2022.108316] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/14/2022] [Revised: 11/20/2022] [Accepted: 11/21/2022] [Indexed: 11/25/2022]
Abstract
The peroxisome proliferator-activated receptor gamma (PPARγ), which belongs to the family of nuclear receptors, has been mainly studied as an important factor in metabolic disorders. However, in recent years the potential role of PPARγ in different neurological diseases has been increasingly investigated. Especially, in the search of therapeutic targets for patients with epilepsy the question of the involvement of PPARγ in seizure control has been raised. Epilepsy is a chronic neurological disorder causing a major impact on the psychological, social, and economic conditions of patients and their families, besides the problems of the disease itself. Considering that the world prevalence of epilepsy ranges between 0.5% - 1.0%, this condition is the fourth for importance among the other neurological disorders, following migraine, stroke, and dementia. Among others, temporal lobe epilepsy (TLE) is the most common form of epilepsy in adult patients. About 65% of individuals who receive antiseizure medications (ASMs) experience seizure independence. For those in whom seizures still recur, investigating PPARγ could lead to the development of novel ASMs. This review focuses on the most important findings from recent investigations about the potential intracellular PPARγ-dependent processes behind different compounds that exhibited anti-seizure effects. Additionally, recent clinical investigations are discussed along with the promising results found for PPARγ agonists and the ketogenic diet (KD) in various rodent models of epilepsy.
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Affiliation(s)
- Lara Senn
- Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy; PhD School of Clinical and Experimental Medicine (CEM), University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Anna-Maria Costa
- Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Rossella Avallone
- Department of Life Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy
| | - Katarzyna Socała
- Department of Animal Physiology and Pharmacology, Institute of Biological Sciences, Maria Curie-Skłodowska University, PL 20-033 Lublin, Poland
| | - Piotr Wlaź
- Department of Animal Physiology and Pharmacology, Institute of Biological Sciences, Maria Curie-Skłodowska University, PL 20-033 Lublin, Poland
| | - Giuseppe Biagini
- Department of Biomedical, Metabolic, and Neural Sciences, University of Modena and Reggio Emilia, 41125 Modena, Italy.
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Ishtiaq SM, Arshad MI, Khan JA. PPARγ signaling in hepatocarcinogenesis: Mechanistic insights for cellular reprogramming and therapeutic implications. Pharmacol Ther 2022; 240:108298. [PMID: 36243148 DOI: 10.1016/j.pharmthera.2022.108298] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Revised: 09/26/2022] [Accepted: 10/04/2022] [Indexed: 11/30/2022]
Abstract
Liver cancer or hepatocellular carcinoma (HCC) is leading cause of cancer-related mortalities globally. The therapeutic approaches for chronic liver diseases-associated liver cancers aimed at modulating immune check-points and peroxisome proliferator-activated receptor gamma (PPARγ) signaling pathway during multistep process of hepatocarcinogenesis that played a dispensable role in immunopathogenesis and outcomes of disease. Herein, the review highlights PPARγ-induced effects in balancing inflammatory (tumor necrosis factor alpha (TNF-α), interleukin (IL)-6, IL-1) and anti-inflammatory cytokines (IL-10, transforming growth factor beta (TGF-β), and interplay of PPARγ, hepatic stellate cells and fibrogenic niche in cell-intrinsic and -extrinsic crosstalk of hepatocarcinogenesis. PPARγ-mediated effects in pre-malignant microenvironment promote growth arrest, cell senescence and cell clearance in liver cancer pathophysiology. Furthermore, PPARγ-immune cell axis of liver microenvironment exhibits an immunomodulation strategy of resident immune cells of the liver (macrophages, natural killer cells, and dendritic cells) in concomitance with current clinical guidelines of the European Association for Study of Liver Diseases (EASL) for several liver diseases. Thus, mechanistic insights of PPARγ-associated high value targets and canonical signaling suggest PPARγ as a possible therapeutic target in reprogramming of hepatocarcinogenesis to decrease burden of liver cancers, worldwide.
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Affiliation(s)
- Syeda Momna Ishtiaq
- Institute of Physiology and Pharmacology, University of Agriculture, Faisalabad 38040, Pakistan
| | | | - Junaid Ali Khan
- Department of Pharmacology and Physiology, MNS University of Agriculture, Multan 60000, Pakistan.
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15
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Martin-Perez M, Urdiroz-Urricelqui U, Bigas C, Benitah SA. The role of lipids in cancer progression and metastasis. Cell Metab 2022; 34:1675-1699. [PMID: 36261043 DOI: 10.1016/j.cmet.2022.09.023] [Citation(s) in RCA: 234] [Impact Index Per Article: 78.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
Lipids have essential biological functions in the body (e.g., providing energy storage, acting as a signaling molecule, and being a structural component of membranes); however, an excess of lipids can promote tumorigenesis, colonization, and metastatic capacity of tumor cells. To metastasize, a tumor cell goes through different stages that require lipid-related metabolic and structural adaptations. These adaptations include altering the lipid membrane composition for invading other niches and overcoming cell death mechanisms and promoting lipid catabolism and anabolism for energy and oxidative stress protective purposes. Cancer cells also harness lipid metabolism to modulate the activity of stromal and immune cells to their advantage and to resist therapy and promote relapse. All this is especially worrying given the high fat intake in Western diets. Thus, metabolic interventions aiming to reduce lipid availability to cancer cells or to exacerbate their metabolic vulnerabilities provide promising therapeutic opportunities to prevent cancer progression and treat metastasis.
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Affiliation(s)
- Miguel Martin-Perez
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain; Department of Cell Biology, Physiology and Immunology, University of Barcelona, 08028 Barcelona, Spain.
| | - Uxue Urdiroz-Urricelqui
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain
| | - Claudia Bigas
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain
| | - Salvador Aznar Benitah
- Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), 08028 Barcelona, Spain; Catalan Institution for Research and Advanced Studies (ICREA), 08010 Barcelona, Spain.
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Tokhanbigli S, Alavifard H, Asadzadeh Aghdaei H, Zali MR, Baghaei K. Combination of pioglitazone and dendritic cell to optimize efficacy of immune cell therapy in CT26 tumor models. BIOIMPACTS : BI 2022; 13:333-346. [PMID: 37645031 PMCID: PMC10460770 DOI: 10.34172/bi.2022.24209] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Revised: 02/28/2022] [Accepted: 06/20/2022] [Indexed: 08/31/2023]
Abstract
Introduction The maturation faith of dendritic cells is restrained by the inflammatory environment and cytokines, such as interleukin-6 and its downstream component. Therefore, introducing the suitable antigen to dendritic cells is crucial. However, reducing the severity of the suppressive tumor microenvironment is indispensable. The present study examined the combination therapy of lymphocyte antigen 6 family member E (LY6E) pulsed mature dendritic cells (LPMDCs) and pioglitazone against colorectal cancer (CRC) to elevate the effectiveness of cancer treatment through probable role of pioglitazone on inhibiting IL-6/STAT3 pathway. Methods Dendritic cells were generated from murine bone marrow and were pulsed with lymphocyte antigen 6 family member E peptide to assess antigen-specific T-cell proliferation and cytotoxicity assay with Annexin/PI. The effect of pioglitazone on interleukin (IL)-6/STAT3 was evaluated in vitro by real-time polymerase chain reaction (PCR). Afterward, the CRC model was established by subcutaneous injection of CT26, mouse colon carcinoma cell line, in female mice. After treatment, tumor, spleen, and lymph nodes samples were removed for histopathological, ELISA, and real-time PCR analysis. Results In vitro results revealed the potential of lysate-pulsed dendritic cells in the proliferation of double-positive CD3-8 splenocytes and inducing immunogenic cell death responses, whereas pioglitazone declined the expression of IL-6/STAT3 in colorectal cell lines. In animal models, the recipient of LPMDCs combined with pioglitazone demonstrated high tumor-infiltrating lymphocytes. Elevating the IL-12 and interferon-gamma (IFN-γ) levels and prolonged survival in lysate-pulsed dendritic cell and combination groups were observed. Conclusion Pioglitazone could efficiently ameliorate the immunosuppressive feature of the tumor microenvironment, mainly through IL-6. Accordingly, applying this drug combined with LPMDCs provoked substantial CD8 positive responses in tumor-challenged animal models.
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Affiliation(s)
- Samaneh Tokhanbigli
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Helia Alavifard
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hamid Asadzadeh Aghdaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Reza Zali
- Gastroenterology and Liver Diseases Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Kaveh Baghaei
- Basic and Molecular Epidemiology of Gastrointestinal Disorders Research Center, Research Institute for Gastroenterology and Liver Diseases, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Wagner N, Wagner KD. Peroxisome Proliferator-Activated Receptors and the Hallmarks of Cancer. Cells 2022; 11:cells11152432. [PMID: 35954274 PMCID: PMC9368267 DOI: 10.3390/cells11152432] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2022] [Revised: 08/02/2022] [Accepted: 08/04/2022] [Indexed: 12/11/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) function as nuclear transcription factors upon the binding of physiological or pharmacological ligands and heterodimerization with retinoic X receptors. Physiological ligands include fatty acids and fatty-acid-derived compounds with low specificity for the different PPAR subtypes (alpha, beta/delta, and gamma). For each of the PPAR subtypes, specific pharmacological agonists and antagonists, as well as pan-agonists, are available. In agreement with their natural ligands, PPARs are mainly focused on as targets for the treatment of metabolic syndrome and its associated complications. Nevertheless, many publications are available that implicate PPARs in malignancies. In several instances, they are controversial for very similar models. Thus, to better predict the potential use of PPAR modulators for personalized medicine in therapies against malignancies, it seems necessary and timely to review the three PPARs in relation to the didactic concept of cancer hallmark capabilities. We previously described the functions of PPAR beta/delta with respect to the cancer hallmarks and reviewed the implications of all PPARs in angiogenesis. Thus, the current review updates our knowledge on PPAR beta and the hallmarks of cancer and extends the concept to PPAR alpha and PPAR gamma.
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Affiliation(s)
- Nicole Wagner
- Correspondence: (N.W.); (K.-D.W.); Tel.: +33-489-153-713 (K.-D.W.)
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18
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Liu C, Huang R, Yu H, Gong Y, Wu P, Feng Q, Li X. Fuzheng Xiaozheng prescription exerts anti-hepatocellular carcinoma effects by improving lipid and glucose metabolisms via regulating circRNA-miRNA-mRNA networks. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2022; 103:154226. [PMID: 35689900 DOI: 10.1016/j.phymed.2022.154226] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/04/2022] [Revised: 05/22/2022] [Accepted: 05/31/2022] [Indexed: 06/15/2023]
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a major threat to human health due to its high lethality. Our previous studies suggested that Fuzheng Xiaozheng prescription (FZXZP), an effective Chinese medicine, demonstrated significant suppressive effects on HCC. However, its underlying mechanism remains largely unclear. PURPOSE This study aimed to investigate the anti-HCC mechanisms of FZXZP from transcriptomic sequencing based on a holistic perspective. METHODS Rat HCC model was induced by diethylnitrosamine, and then the model was administered with two doses of FZXZP, high and low. Sodium demethylcantharidate was used as a positive control. Subsequently, microarrays of circRNA, miRNA and mRNA were performed on the blank, model, high and low dose groups, respectively, and the competitive binding mechanisms among them were further analyzed by bioinformatics. Then, the circRNA-miRNA-mRNA networks were constructed to mine the targeted-RNAs of FZXZP in HCC, as well as to explore their potential regulatory mechanisms. Finally, functions and pathways of the FZXZP targeted genes in rat HCC were annotated with GO and KEGG, and qRT-PCR was performed to validate the accuracy of the above analyses in this study. RESULTS The results showed that FZXZP significantly inhibited the development and progression of HCC in rats, improved the pathological conditions and suppressed the proliferation of HCC cells. Subsequently, after a series of screening, the competing endogenous RNA networks (circRNA-miRNA-mRNA), consisting of 2 circRNAs, 7 miRNAs and 104 mRNAs, were finally established. KEGG and GO analyses of the networks revealed that lipid metabolism related pathways, such as fatty acid metabolism, bile secretion and PPAR pathway, were significantly enriched. In the further hubgene network analysis, in addition to lipid metabolism, aberrant glucose metabolism was found to be ameliorated by G6pc and Pklr in hubgenes. Finally, the qRT-PCR analyses confirmed that the expression tendencies of the above targeted genes were correct and believable in transcriptomic sequencings, and qRT-PCR results of the genes closely related to proliferation, invasion and apoptosis of HCC also indicated the inhibitory effects of FZXZP on HCC obviously. CONCLUSION FZXZP demonstrated significant anti-HCC effects through improving lipid and glucose metabolism, restoring the metabolic homeostasis of the liver via circRNA-miRNA-mRNA networks.
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Affiliation(s)
- Chao Liu
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Renwei Huang
- Sichuan Provincial Key Laboratory for Development and Utilization of Characteristic Horticultural Biological Resources, College of Chemistry and Life Sciences, Chengdu Normal University, Chengdu, 611130, China
| | - Han Yu
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Yanju Gong
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
| | - Peijie Wu
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Quansheng Feng
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China
| | - Xia Li
- School of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu, 611137, China.
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Katoch S, Sharma V, Patial V. Peroxisome proliferator-activated receptor gamma as a therapeutic target for hepatocellular carcinoma: Experimental and clinical scenarios. World J Gastroenterol 2022; 28:3535-3554. [PMID: 36161051 PMCID: PMC9372809 DOI: 10.3748/wjg.v28.i28.3535] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 04/25/2022] [Accepted: 06/24/2022] [Indexed: 02/06/2023] Open
Abstract
Hepatocellular carcinoma (HCC) is the most common type of liver cancer worldwide. Viral hepatitis is a significant risk factor for HCC, although metabolic syndrome and diabetes are more frequently associated with the HCC. With increasing prevalence, there is expected to be > 1 million cases annually by 2025. Therefore, there is an urgent need to establish potential therapeutic targets to cure this disease. Peroxisome-proliferator-activated receptor gamma (PPARγ) is a ligand-activated transcription factor that plays a crucial role in the patho-physiology of HCC. Many synthetic agonists of PPARγ suppress HCC in experimental studies and clinical trials. These synthetic agonists have shown promising results by inducing cell cycle arrest and apoptosis in HCC cells and preventing the invasion and metastasis of HCC. However, some synthetic agonists also pose severe side effects in addition to their therapeutic efficacy. Thus natural PPARγ agonists can be an alternative to exploit this potential target for HCC treatment. In this review, the regulatory role of PPARγ in the pathogenesis of HCC is elucidated. Furthermore, the experimental and clinical scenario of both synthetic and natural PPARγ agonists against HCC is discussed. Most of the available literature advocates PPARγ as a potential therapeutic target for the treatment of HCC.
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Affiliation(s)
- Swati Katoch
- Division of Dietetics and Nutrition Technology, Institute of Himalayan Bioresource Technology, Palampur 176061, Himachal Pradesh, India
- Academy of Scientific and Innovative Research, Ghaziabad 201002, UP, India
| | - Vinesh Sharma
- Division of Dietetics and Nutrition Technology, Institute of Himalayan Bioresource Technology, Palampur 176061, Himachal Pradesh, India
- Academy of Scientific and Innovative Research, Ghaziabad 201002, UP, India
| | - Vikram Patial
- Division of Dietetics and Nutrition Technology, Institute of Himalayan Bioresource Technology, Palampur 176061, Himachal Pradesh, India
- Academy of Scientific and Innovative Research, Ghaziabad 201002, UP, India
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20
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Renal Cell Cancer and Obesity. Int J Mol Sci 2022; 23:ijms23063404. [PMID: 35328822 PMCID: PMC8951303 DOI: 10.3390/ijms23063404] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2022] [Revised: 03/14/2022] [Accepted: 03/16/2022] [Indexed: 02/06/2023] Open
Abstract
Cancers are a frequent cause of morbidity and mortality. There are many risk factors for tumours, including advanced age, personal or family history of cancer, some types of viral infections, exposure to radiation and some chemicals, smoking and alcohol consumption, as well as obesity. Increasing evidence suggest the role of obesity in the initiation and progression of various cancers, including renal cell carcinoma. Since tumours require energy for their uncontrollable growth, it appears plausible that their initiation and development is associated with the dysregulation of cells metabolism. Thus, any state characterised by an intake of excessive energy and nutrients may favour the development of various cancers. There are many factors that promote the development of renal cell carcinoma, including hypoxia, inflammation, insulin resistance, excessive adipose tissue and adipokines and others. There are also many obesity-related alterations in genes expression, including DNA methylation, single nucleotide polymorphisms, histone modification and miRNAs that can promote renal carcinogenesis. This review focuses on the impact of obesity on the risk of renal cancers development, their aggressiveness and patients’ survival.
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Afonso MB, Rodrigues PM, Mateus-Pinheiro M, Simão AL, Gaspar MM, Majdi A, Arretxe E, Alonso C, Santos-Laso A, Jimenez-Agüero R, Eizaguirre E, Bujanda L, Pareja MJ, Banales JM, Ratziu V, Gautheron J, Castro RE, Rodrigues CMP. RIPK3 acts as a lipid metabolism regulator contributing to inflammation and carcinogenesis in non-alcoholic fatty liver disease. Gut 2021; 70:2359-2372. [PMID: 33361348 PMCID: PMC8588316 DOI: 10.1136/gutjnl-2020-321767] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 09/22/2020] [Accepted: 11/25/2020] [Indexed: 12/24/2022]
Abstract
OBJECTIVE Receptor-interacting protein kinase 3 (RIPK3) is a key player in necroptosis execution and an emerging metabolic regulator, whose contribution to non-alcoholic fatty liver disease (NAFLD) is controversial. We aimed to clarify the impact of RIPK3 signalling in the pathogenesis of human and experimental NAFLD. DESIGN RIPK3 levels were evaluated in two large independent cohorts of patients with biopsy proven NAFLD diagnosis and correlated with clinical and biochemical parameters. Wild-type (WT) or Ripk3-deficient (Ripk3-/-) mice were fed a choline-deficient L-amino acid-defined diet (CDAA) or an isocaloric control diet for 32 and 66 weeks. RESULTS RIPK3 increased in patients with non-alcoholic steatohepatitis (NASH) in both cohorts, correlating with hepatic inflammation and fibrosis. Accordingly, Ripk3 deficiency ameliorated CDAA-induced inflammation and fibrosis in mice at both 32 and 66 weeks. WT mice on the CDAA diet for 66 weeks developed preneoplastic nodules and displayed increased hepatocellular proliferation, which were reduced in Ripk3-/- mice. Furthermore, Ripk3 deficiency hampered tumourigenesis. Intriguingly, Ripk3-/- mice displayed increased body weight gain, while lipidomics showed that deletion of Ripk3 shifted hepatic lipid profiles. Peroxisome proliferator-activated receptor γ (PPARγ) was increased in Ripk3-/- mice and negatively correlated with hepatic RIPK3 in patients with NAFLD. Mechanistic studies established a functional link between RIPK3 and PPARγ in controlling fat deposition and fibrosis. CONCLUSION Hepatic RIPK3 correlates with NAFLD severity in humans and mice, playing a key role in managing liver metabolism, damage, inflammation, fibrosis and carcinogenesis. Targeting RIPK3 and its intricate signalling arises as a novel promising approach to treat NASH and arrest disease progression.
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Affiliation(s)
- Marta B Afonso
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Pedro M Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Miguel Mateus-Pinheiro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - André L Simão
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Maria M Gaspar
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Amine Majdi
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine (CRSA), Paris, France
- Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
| | - Enara Arretxe
- OWL Metabolomics, Bizkaia Technology Park, Derio, Spain
| | | | - Alvaro Santos-Laso
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, CIBERehd, San Sebastian, Spain
| | - Raul Jimenez-Agüero
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, CIBERehd, San Sebastian, Spain
| | - Emma Eizaguirre
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, CIBERehd, San Sebastian, Spain
| | - Luis Bujanda
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, CIBERehd, San Sebastian, Spain
| | | | - Jesus M Banales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), Ikerbasque, CIBERehd, San Sebastian, Spain
| | - Vlad Ratziu
- Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
- Department of Hepatology, Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Paris, France
- Sorbonne Université, Inserm, Centre de Recherche des Cordeliers (CRC), Paris, France
| | - Jeremie Gautheron
- Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine (CRSA), Paris, France
- Institute of Cardiometabolism and Nutrition (ICAN), Paris, France
| | - Rui E Castro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Cecília M P Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
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22
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Wang X, Wang Z, Wang Q, Wang B. Modulatory effect of euxanthone in liver cancer-bearing obese mice: crosstalk between PPARγ and TIMP3 signalling axes. 3 Biotech 2021; 11:464. [PMID: 34745815 DOI: 10.1007/s13205-021-03019-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 10/06/2021] [Indexed: 10/20/2022] Open
Abstract
Liver cancer is one of the prominent cancer-associated fatal diseases with > 80% of cases befall in low-middle resource nations worldwide. In the current study, we studied the effect of euxanthone (EUX) on obesity-associated liver cancer using a high-fat diet-fed mouse model of diethylnitrosamine (DEN)-provoked hepatocellular carcinoma. Mice with 2 weeks of age were intraperitoneally injected with diethylnitrosamine (DEN) 25 mg/kg b.w. After 4 weeks, the mice were divided into four groups with low-fat diet (LFD), high-fat diet (HFD), and EUX treatment groups with or without PPARγ inhibitor (GW9662). We observed that TIMP3, E-cadherin, and Klotho expressions were downmodulated, while MMP9, ADAM17, and Wnt signalling biofactors (Wnt5a, Wnt3a and β-catenin) were upmodulated in the HFD groups. Nevertheless, these aberrations were reciprocated by the treatment with EUX; at the same time, co-administration of PPARγ inhibitor ablated the anti-cancer effects of EUX, indicating that PPARγ activation is a pivotal mechanism underpinning the negative regulation of oncogenic factors by EUX. Together, these results imply that EUX might be a viable therapeutic option in the treatment of obesity-associated hepatocarcinogenesis.
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Peroxisome Proliferator-Activated Receptor γ, but Not α or G-Protein Coupled Estrogen Receptor Drives Functioning of Postnatal Boar Testis-Next Generation Sequencing Analysis. Animals (Basel) 2021; 11:ani11102868. [PMID: 34679887 PMCID: PMC8532933 DOI: 10.3390/ani11102868] [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] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 09/19/2021] [Accepted: 09/27/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary As of now, the Next Generation Sequencing (NGS) analysis has not been utilized to identify biological processes and signaling pathways that are regulated in the boar postnatal testes. Our prior studies revealed that the peroxisome proliferator-activated receptor (PPAR) and G-protein coupled estrogen receptor (GPER) were significant for the morpho-functional status of testicular cells. Here, the pharmacological blockage of PPARα, PPARγ or GPER was performed in ex vivo immature boar testes. The NGS results showed 382 transcripts with an altered expression. The blockage by the PPARγ antagonist markedly affected biological processes such as: drug metabolism (genes: Ctsh, Duox2, Atp1b1, Acss2, Pkd2, Aldh2, Hbb, Sdhd, Cox3, Nd4, Nd5, Cytb, Cbr1, and Pid1), adhesion (genes: Plpp3, Anxa1, Atp1b1, S100a8, Cd93, Ephb4, Vsir, Cldn11, Gpc4, Fermt3, Dusp26, Sox9, and Cdh5) and tube development (genes: Ctsh, Mmp14, Dll4, Anxa1, Ephb4, Pkd2, Angptl4, Robo4, Sox9, Hikeshi, Ing2, Loc100738836, and Rarres2), as well as the Notch signaling pathway. This was not the case for the PPARα or GPER antagonists. Our observations suggested that PPARγ may be the principal player in the management of the development and function of boar testes during the early postnatal window. Moreover, due to a highly similar porcine gene expression pattern to human homologues genes, our results can be used to understand both animal and human testes physiology and to predict or treat pathological processes. Abstract Porcine tissue gene expression is highly similar to the expression of homologous genes in humans. Based on this fact, the studies on porcine tissues can be employed to understand human physiology and to predict or treat diseases. Our prior studies clearly showed that there was a regulatory partnership of the peroxisome proliferator-activated receptor (PPAR) and the G-protein coupled membrane estrogen receptor (GPER) that relied upon the tumorigenesis of human and mouse testicular interstitial cells, as well as the PPAR-estrogen related receptor and GPER–xenoestrogen relationships which affected the functional status of immature boar testes. The main objective of this study was to identify the biological processes and signaling pathways governed by PPARα, PPARγ and GPER in the immature testes of seven-day-old boars after pharmacological receptor ligand treatment. Boar testicular tissues were cultured in an organotypic system with the respective PPARα, PPARγ or GPER antagonists. To evaluate the effect of the individual receptor deprivation in testicular tissue on global gene expression, Next Generation Sequencing was performed. Bioinformatic analysis revealed 382 transcripts with altered expression. While tissues treated with PPARα or GPER antagonists showed little significance in the enrichment analysis, the antagonists challenged with the PPARγ antagonist displayed significant alterations in biological processes such as: drug metabolism, adhesion and tubule development. Diverse disruption in the Notch signaling pathway was also observed. The findings of our study proposed that neither PPARα nor GPER, but PPARγ alone seemed to be the main player in the regulation of boar testes functioning during early the postnatal developmental window.
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24
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Loo SY, Syn NL, Koh APF, Teng JCF, Deivasigamani A, Tan TZ, Thike AA, Vali S, Kapoor S, Wang X, Wang JW, Tan PH, Yip GW, Sethi G, Huang RYJ, Hui KM, Wang L, Goh BC, Kumar AP. Epigenetic derepression converts PPARγ into a druggable target in triple-negative and endocrine-resistant breast cancers. Cell Death Discov 2021; 7:265. [PMID: 34580286 PMCID: PMC8476547 DOI: 10.1038/s41420-021-00635-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2021] [Revised: 08/23/2021] [Accepted: 09/03/2021] [Indexed: 01/04/2023] Open
Abstract
Clinical trials repurposing peroxisome proliferator-activated receptor-gamma (PPARγ) agonists as anticancer agents have exhibited lackluster efficacy across a variety of tumor types. Here, we report that increased PPARG expression is associated with a better prognosis but is anticorrelated with histone deacetylase (HDAC) 1 and 2 expressions. We show that HDAC overexpression blunts anti-proliferative and anti-angiogenic responses to PPARγ agonists via transcriptional and post-translational mechanisms, however, these can be neutralized with clinically approved and experimental HDAC inhibitors. Supporting this notion, concomitant treatment with HDAC inhibitors was required to license the tumor-suppressive effects of PPARγ agonists in triple-negative and endocrine-refractory breast cancer cells, and combination therapy also restrained angiogenesis in a tube formation assay. This combination was also synergistic in estrogen receptor-alpha (ERα)-positive cells because HDAC blockade abrogated ERα interference with PPARγ-regulated transcription. Following a pharmacokinetics optimization study, the combination of rosiglitazone and a potent pan-HDAC inhibitor, LBH589, stalled disease progression in a mouse model of triple-negative breast cancer greater than either of the monotherapies, while exhibiting a favorable safety profile. Our findings account for historical observations of de-novo resistance to PPARγ agonist monotherapy and propound a therapeutically cogent intervention against two aggressive breast cancer subtypes.
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Affiliation(s)
- Ser Yue Loo
- Cancer Science Institute of Singapore and Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Genome Institute of Singapore, A*STAR, Singapore, Singapore
| | - Nicholas L Syn
- Department of Haematology-Oncology, National University Cancer Institute, Singapore, Singapore.,Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Angele Pei-Fern Koh
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Janet Cheng-Fei Teng
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Amudha Deivasigamani
- Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore, Singapore
| | - Tuan Zea Tan
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Aye Aye Thike
- Department of Pathology, Singapore General Hospital, Singapore, Singapore
| | - Shireen Vali
- Cellworks Research India Pvt. Ltd., Bengaluru, India
| | - Shweta Kapoor
- Cellworks Research India Pvt. Ltd., Bengaluru, India
| | - Xiaoyuan Wang
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Cardiovascular Research Institute (CVRI), National University Heart Centre, Singapore (NUHCS), National University Health System, Singapore, Singapore
| | - Jiong Wei Wang
- Department of Surgery, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Puay Hoon Tan
- Department of Pathology, Singapore General Hospital, Singapore, Singapore
| | - George W Yip
- Department of Anatomy, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
| | - Ruby Yun-Ju Huang
- School of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan
| | - Kam Man Hui
- Division of Cellular and Molecular Research, National Cancer Centre Singapore, Singapore, Singapore
| | - Lingzhi Wang
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
| | - Boon Cher Goh
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore.,Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.,National University Cancer Institute, National University Health System, Singapore, Singapore.,Department of Haematology-Oncology, National University Hospital, National University Health System, Singapore, Singapore
| | - Alan Prem Kumar
- Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore. .,NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore. .,National University Cancer Institute, National University Health System, Singapore, Singapore.
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25
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Esmaeili S, Salari S, Kaveh V, Ghaffari SH, Bashash D. Alteration of PPAR-GAMMA (PPARG; PPARγ) and PTEN gene expression in acute myeloid leukemia patients and the promising anticancer effects of PPARγ stimulation using pioglitazone on AML cells. Mol Genet Genomic Med 2021; 9:e1818. [PMID: 34549887 PMCID: PMC8606220 DOI: 10.1002/mgg3.1818] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2021] [Revised: 05/10/2021] [Accepted: 09/07/2021] [Indexed: 12/22/2022] Open
Abstract
Background In the new era of tailored cancer treatment strategies, finding a molecule to regulate a wide range of intracellular functions is valuable. The unique property of nuclear receptor peroxisome proliferator‐activated receptor‐γ (PPARγ; PPARG) in transmitting the anti‐survival signals of the chemotherapeutic drugs has fired the enthusiasm into the application of this receptor in cancer treatment. Objectives We aimed to investigate the expression of PPARγ and one of its downstream targets PTEN in non‐M3 acute myeloid leukemia (AML) patients. We also investigated the therapeutic value of PPARγ stimulation using pioglitazone in the AML‐derived U937 cell line. Methods The blood samples from 30 patients diagnosed with non‐M3 AML as well as 10 healthy individuals were collected and the mRNA expression levels of PPARγ and PTEN were evaluated. Additionally, we used trypan blue assay, MTT assay, and flow cytometry analysis to evaluate the anti‐leukemic effects of pioglitazone on U937 cells. Results While PTEN was significantly downregulated in AML patients as compared to the control group, the expression of PPARγ was increased in the patients’ group. The expression level of PPARγ was also negatively correlated with PTEN; however, it was not statistically significant. Besides, PPARγ stimulation using pioglitazone reduced survival and proliferative capacity of U937 cells through inducing apoptosis and suppression of cell transition from the G1 phase of the cell cycle. Conclusion The results of the present study shed more light on the importance of PPARγ and its stimulation in the therapeutic strategies of AML.
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Affiliation(s)
- Shadi Esmaeili
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Sina Salari
- Department of Medical Oncology, Hematology and Bone Marrow Transplantation, Taleghani Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Vahid Kaveh
- Department of Medical Oncology and Hematology, Iran University of Medical Sciences, Tehran, Iran
| | - Seyed H Ghaffari
- Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
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Monroy-Ramirez HC, Galicia-Moreno M, Sandoval-Rodriguez A, Meza-Rios A, Santos A, Armendariz-Borunda J. PPARs as Metabolic Sensors and Therapeutic Targets in Liver Diseases. Int J Mol Sci 2021; 22:ijms22158298. [PMID: 34361064 PMCID: PMC8347792 DOI: 10.3390/ijms22158298] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/28/2021] [Accepted: 07/29/2021] [Indexed: 12/12/2022] Open
Abstract
Carbohydrates and lipids are two components of the diet that provide the necessary energy to carry out various physiological processes to help maintain homeostasis in the body. However, when the metabolism of both biomolecules is altered, development of various liver diseases takes place; such as metabolic-associated fatty liver diseases (MAFLD), hepatitis B and C virus infections, alcoholic liver disease (ALD), and in more severe cases, hepatocelular carcinoma (HCC). On the other hand, PPARs are a family of ligand-dependent transcription factors with an important role in the regulation of metabolic processes to hepatic level as well as in other organs. After interaction with specific ligands, PPARs are translocated to the nucleus, undergoing structural changes to regulate gene transcription involved in lipid metabolism, adipogenesis, inflammation and metabolic homeostasis. This review aims to provide updated data about PPARs’ critical role in liver metabolic regulation, and their involvement triggering the genesis of several liver diseases. Information is provided about their molecular characteristics, cell signal pathways, and the main pharmacological therapies that modulate their function, currently engaged in the clinic scenario, or in pharmacological development.
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Affiliation(s)
- Hugo Christian Monroy-Ramirez
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (H.C.M.-R.); (M.G.-M.); (A.S.-R.)
| | - Marina Galicia-Moreno
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (H.C.M.-R.); (M.G.-M.); (A.S.-R.)
| | - Ana Sandoval-Rodriguez
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (H.C.M.-R.); (M.G.-M.); (A.S.-R.)
| | - Alejandra Meza-Rios
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Zapopan 45138, Jalisco, Mexico; (A.M.-R.); (A.S.)
| | - Arturo Santos
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Zapopan 45138, Jalisco, Mexico; (A.M.-R.); (A.S.)
| | - Juan Armendariz-Borunda
- Instituto de Biologia Molecular en Medicina, Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Guadalajara 44340, Jalisco, Mexico; (H.C.M.-R.); (M.G.-M.); (A.S.-R.)
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Zapopan 45138, Jalisco, Mexico; (A.M.-R.); (A.S.)
- Correspondence:
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27
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Orabi D, Berger NA, Brown JM. Abnormal Metabolism in the Progression of Nonalcoholic Fatty Liver Disease to Hepatocellular Carcinoma: Mechanistic Insights to Chemoprevention. Cancers (Basel) 2021; 13:3473. [PMID: 34298687 PMCID: PMC8307710 DOI: 10.3390/cancers13143473] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 07/01/2021] [Accepted: 07/02/2021] [Indexed: 02/07/2023] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is on the rise and becoming a major contributor to the development of hepatocellular carcinoma (HCC). Reasons for this include the rise in obesity and metabolic syndrome in contrast to the marked advances in prevention and treatment strategies of viral HCC. These shifts are expected to rapidly propel this trend even further in the coming decades, with NAFLD on course to become the leading etiology of end-stage liver disease and HCC. No Food and Drug Administration (FDA)-approved medications are currently available for the treatment of NAFLD, and advances are desperately needed. Numerous medications with varying mechanisms of action targeting liver steatosis and fibrosis are being investigated including peroxisome proliferator-activated receptor (PPAR) agonists and farnesoid X receptor (FXR) agonists. Additionally, drugs targeting components of metabolic syndrome, such as antihyperglycemics, have been found to affect NAFLD progression and are now being considered in the treatment of these patients. As NAFLD drug discovery continues, special attention should be given to their relationship to HCC. Several mechanisms in the pathogenesis of NAFLD have been implicated in hepatocarcinogenesis, and therapies aimed at NAFLD may additionally harbor independent antitumorigenic potential. This approach may provide novel prevention and treatment strategies.
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Affiliation(s)
- Danny Orabi
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland Clinic, Cleveland, OH 44106, USA;
- Center for Microbiome and Human Health, Lerner Research Institute of the Cleveland Clinic, Cleveland, OH 44106, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA
- Case Comprehensive Cancer Center, Cleveland, OH 44106, USA;
- Department of General Surgery, Cleveland Clinic, Cleveland, OH 44195, USA
| | - Nathan A. Berger
- Case Comprehensive Cancer Center, Cleveland, OH 44106, USA;
- Department of Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
- Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
- Department of Genetics and Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - J. Mark Brown
- Department of Cardiovascular and Metabolic Sciences, Lerner Research Institute of the Cleveland Clinic, Cleveland, OH 44106, USA;
- Center for Microbiome and Human Health, Lerner Research Institute of the Cleveland Clinic, Cleveland, OH 44106, USA
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH 44195, USA
- Case Comprehensive Cancer Center, Cleveland, OH 44106, USA;
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28
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Xu Z, Meng SH, Bai JG, Sun C, Zhao LL, Tang RF, Yin ZL, Ji JW, Yang W, Ma GJ. C/EBPα Regulates FOXC1 to Modulate Tumor Growth by Interacting with PPARγ in Hepatocellular Carcinoma. Curr Cancer Drug Targets 2021; 20:59-66. [PMID: 31512996 DOI: 10.2174/1568009619666190912161003] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2019] [Revised: 05/28/2019] [Accepted: 07/01/2019] [Indexed: 01/17/2023]
Abstract
BACKGROUND Forkhead box C1 (FOXC1) is an important cancer-associated gene in tumor. PPAR-γ and C/EBPα are both transcriptional regulators involved in tumor development. OBJECTIVE We aimed to clarify the function of PPAR-γ, C/EBPα in hepatocellular carcinoma (HCC) and the relationship of PPAR-γ, C/EBPα and FOXC1 in HCC. METHODS Western blotting, immunofluorescent staining, and immunohistochemistry were used to evaluate protein expression. qRT-PCR was used to assess mRNA expression. Co-IP was performed to detect the protein interaction. And ChIP and fluorescent reporter detection were used to determine the binding between protein and FOXC1 promoter. RESULTS C/EBPα could bind to FOXC1 promoter and PPAR-γ could strengthen C/EBPα's function. Expressions of C/EBPα and PPAR-γ were both negatively related to FOXC1 in human HCC tissue. Confocal displayed that C/EBPα was co-located with FOXC1 in HepG2 cells. C/EBPα could bind to FOXC1 promoter by ChIP. Luciferase activity detection exhibited that C/EBPα could inhibit FOXC1 promoter activity, especially FOXC1 promoter from -600 to -300 was the critical binding site. Only PPAR-γ could not influence luciferase activity but strengthen inhibited effect of C/EBPα. Further, the Co-IP displayed that PPAR-γ could bind to C/EBPα. When C/EBPα and PPAR-γ were both high expressed, cell proliferation, migration, invasion, and colony information were inhibited enormously. C/EBPα plasmid combined with or without PPAR-γ agonist MDG548 treatment exhibited a strong tumor inhibition and FOXC1 suppression in mice. CONCLUSION Our data establish C/EBPα targeting FOXC1 as a potential determinant in the HCC, which supplies a new pathway to treat HCC. However, PPAR-γ has no effect on FOXC1 expression.
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Affiliation(s)
- Zhuo Xu
- Department of Hepatobiliary Surgery, the Fourth Hospital of Hebei Medical University, China
| | - Shao-Hua Meng
- Second Department of Abdominal Surgery, First Affiliated Hospital of Xingtai Medical College, China
| | - Jian-Guo Bai
- Department of Hepatobiliary Surgery, the Fourth Hospital of Hebei Medical University, China
| | - Chao Sun
- Department of Hepatobiliary Surgery, the Fourth Hospital of Hebei Medical University, China
| | - Li-Li Zhao
- National Engineering Laboratory of High Level Expression in Mammalian Cells, Lunan Pharmaceutical Group Co., Ltd., Linyi 276000, China
| | - Rui-Feng Tang
- Department of Hepatobiliary Surgery, the Fourth Hospital of Hebei Medical University, China
| | - Zhao-Lin Yin
- Department of Ultrasound, the Fourth Hospital of Hebei Medical University, China
| | - Jun-Wei Ji
- Department of Emergency, The Fourth Hospital of Hebei Medical University, Hebei, China
| | - Wei Yang
- Department of Hepatobiliary Surgery, the Fourth Hospital of Hebei Medical University, China
| | - Guang-Jun Ma
- Department of Hepatobiliary Surgery, the Fourth Hospital of Hebei Medical University, China
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Cheng HS, Yip YS, Lim EKY, Wahli W, Tan NS. PPARs and Tumor Microenvironment: The Emerging Roles of the Metabolic Master Regulators in Tumor Stromal-Epithelial Crosstalk and Carcinogenesis. Cancers (Basel) 2021; 13:2153. [PMID: 33946986 PMCID: PMC8125182 DOI: 10.3390/cancers13092153] [Citation(s) in RCA: 39] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2021] [Revised: 04/26/2021] [Accepted: 04/26/2021] [Indexed: 12/17/2022] Open
Abstract
Peroxisome proliferator-activated receptors (PPARs) have been extensively studied for more than three decades. Consisting of three isotypes, PPARα, γ, and β/δ, these nuclear receptors are regarded as the master metabolic regulators which govern many aspects of the body energy homeostasis and cell fate. Their roles in malignancy are also increasingly recognized. With the growing interest in crosstalk between tumor stroma and epithelium, this review aims to highlight the current knowledge on the implications of PPARs in the tumor microenvironment. PPARγ plays a crucial role in the metabolic reprogramming of cancer-associated fibroblasts and adipocytes, coercing the two stromal cells to become substrate donors for cancer growth. Fibroblast PPARβ/δ can modify the risk of tumor initiation and cancer susceptibility. In endothelial cells, PPARβ/δ and PPARα are pro- and anti-angiogenic, respectively. Although the angiogenic role of PPARγ remains ambiguous, it is a crucial regulator in autocrine and paracrine signaling of cancer-associated fibroblasts and tumor-associated macrophages/immune cells. Of note, angiopoietin-like 4 (ANGPTL4), a secretory protein encoded by a target gene of PPARs, triggers critical oncogenic processes such as inflammatory signaling, extracellular matrix derangement, anoikis resistance and metastasis, making it a potential drug target for cancer treatment. To conclude, PPARs in the tumor microenvironment exhibit oncogenic activities which are highly controversial and dependent on many factors such as stromal cell types, cancer types, and oncogenesis stages. Thus, the success of PPAR-based anticancer treatment potentially relies on innovative strategies to modulate PPAR activity in a cell type-specific manner.
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Affiliation(s)
- Hong Sheng Cheng
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore; (Y.S.Y.); (W.W.)
| | - Yun Sheng Yip
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore; (Y.S.Y.); (W.W.)
| | - Eldeen Kai Yi Lim
- School of Biological Sciences, Nanyang Technological University Singapore, 60 Nanyang Drive, Singapore 637551, Singapore;
| | - Walter Wahli
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore; (Y.S.Y.); (W.W.)
- Toxalim (Research Center in Food Toxicology), INRAE, ENVT, INP-PURPAN, UMR 1331, UPS, Université de Toulouse, 31300 Toulouse, France
- Center for Integrative Genomics, Université de Lausanne, Le Génopode, CH-1015 Lausanne, Switzerland
| | - Nguan Soon Tan
- Lee Kong Chian School of Medicine, Nanyang Technological University Singapore, 11 Mandalay Road, Singapore 308232, Singapore; (Y.S.Y.); (W.W.)
- School of Biological Sciences, Nanyang Technological University Singapore, 60 Nanyang Drive, Singapore 637551, Singapore;
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30
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Hang T, Yang L, Zhang X, Li J, Long F, Zhu N, Li Y, Xia J, Zhang Y, Zhang P, Zhang Y, Wei X, Li S. Peroxisome proliferator-activated receptor γ improves pemetrexed therapeutic efficacy in non-squamous non-small cell lung cancer. Am J Transl Res 2021; 13:2296-2307. [PMID: 34017390 PMCID: PMC8129360] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 01/20/2021] [Indexed: 06/12/2023]
Abstract
OBJECTIVE The folic acid analog pemetrexed (PMX) is recommended for the first-line chemotherapy for advanced non-squamous non-small cell lung cancer (NSCLC). However, the mechanisms underlying PMX cytotoxicity in NSCLC remain to be fully explored. METHODS PMX effect was evaluated in a urethane-induced lung adenocarcinoma mouse model. The interaction between PMX and intracellular proteins, particularly peroxisome proliferator-activated receptor γ (PPARγ), was investigated. The role of PPARγ in mediating pemetrexed cytotoxicity was investigated using NSCLC cell lines, mouse models and clinical specimens. RESULTS This study found that PPARγ expression was correlated with prolonged progression-free survival in NSCLC patients. PPARγ downregulated hypoxanthine-guanine phosphoribosyl transferase (HGPRT), a key enzyme for nucleotide salvage synthesis, thereby sensitizing cells to PMX inhibition on nucleotide de novo synthesis. PMX was also a candidate partial agonist of PPARγ, and PMX-activated PPARγ bound to NF-κB and transcriptionally suppressed the NF-κB target gene, c-Myc. PMX inhibited tumor growth by activating PPARγ in a urethane-induced lung cancer model characterized by elevated NF-κB activity. CONCLUSION PPARγ improves pemetrexed therapeutic efficacy in non-squamous NSCLC. The cytotoxicity effect of PMX can be synergized by activating PPARγ and thereby inhibiting NF-κB pathway.
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Affiliation(s)
- Tianxing Hang
- Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan UniversityShanghai, China
- Department of Tuberculosis, The Second Hospital of Nanjing, Nanjing University of Chinese MedicineNanjing, China
| | - Li Yang
- Department of Anesthesiology, Changzheng Hospital, Navy Medical University of Chinese PLAShanghai, China
| | - Xiujuan Zhang
- Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan UniversityShanghai, China
| | - Jing Li
- Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan UniversityShanghai, China
| | - Feng Long
- Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan UniversityShanghai, China
| | - Ning Zhu
- Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan UniversityShanghai, China
| | - Ying Li
- Department of Respiratory Medicine, Shaanxi Provincial Second People’s HospitalXi’an, China
| | - Jingwen Xia
- Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan UniversityShanghai, China
| | - Youzhi Zhang
- Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan UniversityShanghai, China
| | - Peng Zhang
- Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan UniversityShanghai, China
| | - Yuanyuan Zhang
- Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan UniversityShanghai, China
| | - Xiaomin Wei
- Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan UniversityShanghai, China
| | - Shengqing Li
- Department of Pulmonary and Critical Care Medicine, Huashan Hospital, Fudan UniversityShanghai, China
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Luo S, Jiang X, Yin G, Liu Y, Liu Z, Meng L, Wu J, Wu H. The herbal agent plantamajoside, exerts a potential inhibitory effect on the development of hepatocellular carcinoma. Exp Ther Med 2021; 21:573. [PMID: 33850545 PMCID: PMC8027734 DOI: 10.3892/etm.2021.10005] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2018] [Accepted: 02/11/2021] [Indexed: 12/23/2022] Open
Abstract
Plantamajoside (PMS), a major component of Plantago asiatica L, has several pharmacological properties, including anti-proliferative, anti-inflammatory and anti-tumor effects. However, the effects of PMS on hepatocellular carcinoma (HCC) have yet to be determined. The aim of the present study was to investigate the effects of PMS on HCC and elucidate the underlying mechanism. All assays were conducted using 5 groups, namely control, sorafenib, and PMS 100, 50, and 25 µg/ml groups. Cell proliferation was determined by the MTT assay. Cell migration was evaluated with the wound healing and Transwell assays, respectively. Cell apoptosis and cell cycle distribution were evaluated via flow cytometry. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) analysis and western blotting were used to further investigate the mechanism of action of PMS. Sorafenib and PMS both significantly attenuated the proliferation and migration of HCC cells, and markedly promoted cell apoptosis. PMS induced cell cycle arrest in the G0/G1 phase. The efficacy of PMS increased in a dose-dependent manner. Further study evaluated the expression of peroxisome proliferator-activated receptor (PPARγ), nuclear factor (NF)-κB and cyclooxygenase (Cox-2) using RT-qPCR analysis and western blotting. The results demonstrated that PMS promoted the expression of PPARγ and suppressed the expression of NF-κB and Cox-2. In conclusion, PMS was shown to affect cell proliferation, migration, apoptosis and cell cycle distribution. Furthermore, PMS promoted the expression of PPARγ and inhibited the expression of NF-κB and Cox-2, which may be the mechanism underlying its biological effects. Based on the results of the present study, PMS appears to be a promising agent for HCC therapy.
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Affiliation(s)
- Shu Luo
- Department of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Xing Jiang
- Department of Nursing, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Gang Yin
- Department of Science and Technology, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Yajun Liu
- Department of Gastroenterology, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, P.R. China
| | - Zhou Liu
- Department of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Linglian Meng
- Department of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
| | - Jian Wu
- Central Laboratory, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210029, P.R. China
| | - Haoxin Wu
- Department of Traditional Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210023, P.R. China
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Yu Q, Wu L, Ji J, Feng J, Dai W, Li J, Wu J, Guo C. Gut Microbiota, Peroxisome Proliferator-Activated Receptors, and Hepatocellular Carcinoma. J Hepatocell Carcinoma 2020; 7:271-288. [PMID: 33150145 PMCID: PMC7605923 DOI: 10.2147/jhc.s277870] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 10/10/2020] [Indexed: 12/12/2022] Open
Abstract
Hepatocellular carcinoma (HCC) is one of the most common malignant tumors in the world. HCC incidence rate is sixth and mortality is fourth worldwide. However, HCC pathogenesis and molecular mechanisms remain unclear. The incidence of HCC is associated with genetic, environmental, and metabolic factors. The role of gut microbiota in the pathogenesis of HCC has attracted researchers' attention because of anatomical and functional interactions between liver and intestine. Studies have demonstrated the involvement of gut microbiota in the development of HCC and chronic liver diseases, such as alcoholic liver disease (ALD), nonalcoholic fatty liver disease (NAFLD), and liver cirrhosis. Peroxisome proliferator-activated receptors (PPARs) are a group of receptors with diverse biological functions. Natural and synthetic PPAR agonists show potential for treatment of NAFLD, liver fibrosis, and HCC. Recent studies have demonstrated that PPARs take part in gut microbiota inhabitation and adaptation. This manuscript reviews the role of gut microbiota in the development of HCC and precancerous diseases, the role of PPARs in modulation of gut microbiota and HCC, and potential of gut microbiota for HCC diagnosis and treatment.
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Affiliation(s)
- Qiang Yu
- Department of Gastroenterology, Putuo People’s Hospital, Tongji University School of Medicine, Shanghai200060, People’s Republic of China
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai200072, People’s Republic of China
| | - Liwei Wu
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai200072, People’s Republic of China
| | - Jie Ji
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai200072, People’s Republic of China
| | - Jiao Feng
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai200072, People’s Republic of China
| | - Weiqi Dai
- Department of Gastroenterology, Putuo People’s Hospital, Tongji University School of Medicine, Shanghai200060, People’s Republic of China
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai200072, People’s Republic of China
- Shanghai Tongren Hospital, Shanghai Jiaotong University School of Medicine, Shanghai200336, People’s Republic of China
| | - Jingjing Li
- Department of Gastroenterology, Putuo People’s Hospital, Tongji University School of Medicine, Shanghai200060, People’s Republic of China
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai200072, People’s Republic of China
| | - Jianye Wu
- Department of Gastroenterology, Putuo People’s Hospital, Tongji University School of Medicine, Shanghai200060, People’s Republic of China
| | - Chuanyong Guo
- Department of Gastroenterology, Putuo People’s Hospital, Tongji University School of Medicine, Shanghai200060, People’s Republic of China
- Department of Gastroenterology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai200072, People’s Republic of China
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Toraih EA, Fawzy MS, Abushouk AI, Shaheen S, Hobani YH, Alruwetei AM, A Mansouri O, Kandil E, Badran DI. Prognostic value of the miRNA-27a and PPAR/RXRα signaling axis in patients with thyroid carcinoma. Epigenomics 2020; 12:1825-1843. [PMID: 32969715 DOI: 10.2217/epi-2020-0167] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023] Open
Abstract
The authors aimed to evaluate the prognostic value of miRNA-27a (miR-27a), peroxisome proliferator-activated receptor alpha/gamma (PPARα/γ) and retinoid X receptor alpha (RXRα) tissue expression in patients with thyroid carcinoma. The expression levels were quantified in 174 archived thyroid specimens using real-time quantitative PCR. Downregulation of miR-27a was associated with lymph node stage and multifocality. PPARα expression was associated with histopathological type, tumor size and lymph node invasion. Moreover, RXRα expression was lower in patients who underwent total/subtotal thyroidectomy or received radioactive iodine treatment. Patients with upregulated miR-27a and downregulated RXRα showed a higher frequency of advanced lymph node stage and relapse by cluster analysis. Both miR-27a and PPARα/RXRα showed association with different poor prognostic indices in thyroid cancer patients.
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Affiliation(s)
- Eman A Toraih
- Department of Surgery, Tulane University, School of Medicine, New Orleans, LA 70112, USA.,Department of Histology & Cell Biology, Genetics Unit, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
| | - Manal S Fawzy
- Department of Medical Biochemistry & Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt.,Department of Biochemistry, Faculty of Medicine, Northern Border University, Arar 1321, Saudi Arabia
| | | | - Sameerah Shaheen
- Department of Anatomy & Stem Cell Unit, College of Medicine, King Saud University, Riyadh 11362, Saudi Arabia
| | - Yahya H Hobani
- Medical Laboratory Technology, College of Applied Medical Sciences, Jazan University, Jazan 45142, KSA
| | - Abdulmohsen M Alruwetei
- Department of Medical Laboratory, College of Applied Medical Sciences, Qassim University, Qassim 51452, Saudi Arabia
| | - Omniah A Mansouri
- Department of Biology, University of Jeddah, College of Science, Jeddah, 21959, Saudi Arabia
| | - Emad Kandil
- Department of Surgery, Division of Endocrine & Oncologic Surgery, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Dahlia I Badran
- Department of Medical Biochemistry & Molecular Biology, Faculty of Medicine, Suez Canal University, Ismailia 41522, Egypt
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Yip TCF, Wong VWS, Chan HLY, Tse YK, Hui VWK, Liang LY, Lee HW, Lui GCY, Kong APS, Wong GLH. Thiazolidinediones reduce the risk of hepatocellular carcinoma and hepatic events in diabetic patients with chronic hepatitis B. J Viral Hepat 2020; 27:904-914. [PMID: 32340077 DOI: 10.1111/jvh.13307] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2020] [Revised: 03/27/2020] [Accepted: 04/05/2020] [Indexed: 12/22/2022]
Abstract
Thiazolidinediones (TZDs) improve glycaemic control and ameliorate liver steatosis, inflammation and fibrosis in patients with fatty liver disease. We aimed to study the impact of TZD and glycaemic control on the risk of hepatocellular carcinoma (HCC) and hepatic events in diabetic patients with chronic hepatitis B (CHB). We performed a retrospective cohort study on diabetic patients with CHB in 2000-2017 using a territory-wide electronic healthcare database in Hong Kong. Diabetes mellitus was identified by use of any antidiabetic medication, haemoglobin A1c (HbA1c ) ≥6.5%, fasting glucose ≥7 mmol/L in two measurements or ≥11.1 mmol/L in one measurement and/or diagnosis codes. Use of antidiabetic medications was modelled as time-dependent covariates. Of 28 999 diabetic patients with CHB, 3963 (13.7%) developed liver-related events (a composite endpoint of HCC and hepatic events) at a median (interquartile range) follow-up of 7.1 (3.7-11.8) years; 1153 patients received TZD during follow-up. After adjusted for important confounders, TZD use was associated with a reduced risk of liver-related events (adjusted hazard ratio [aHR] 0.46, 95% confidence interval [CI] 0.24-0.88; P = .019). Similar trends were observed in HCC (aHR 0.57) and hepatic events (aHR 0.35) separately. Compared to HbA1c of 6.5% at baseline, patients with HbA1c ≥7% had an increased risk of liver-related events; the risk further increased in 5795 (20.0%) patients with HbA1c ≥9% at baseline (aHR 1.14, 95% CI 1.04-1.26; P = .006). TZD use is associated with a lower risk of liver-related events in diabetic patients with CHB. Liver-related events are more common in patients with high HbA1c levels.
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Affiliation(s)
- Terry Cheuk-Fung Yip
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Vincent Wai-Sun Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Henry Lik-Yuen Chan
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Yee-Kit Tse
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Vicki Wing-Ki Hui
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Lilian Yan Liang
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Hye Won Lee
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - Grace Chung-Yan Lui
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Alice Pik-Shan Kong
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Grace Lai-Hung Wong
- Institute of Digestive Disease, The Chinese University of Hong Kong, Hong Kong SAR, China
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong SAR, China
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Wei Q, Qian Y, Yu J, Wong CC. Metabolic rewiring in the promotion of cancer metastasis: mechanisms and therapeutic implications. Oncogene 2020; 39:6139-6156. [PMID: 32839493 PMCID: PMC7515827 DOI: 10.1038/s41388-020-01432-7] [Citation(s) in RCA: 109] [Impact Index Per Article: 21.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2020] [Revised: 07/22/2020] [Accepted: 08/13/2020] [Indexed: 12/19/2022]
Abstract
Tumor metastasis is the major cause of mortality from cancer. Metabolic rewiring and the metastatic cascade are highly intertwined, co-operating to promote multiple steps of cancer metastasis. Metabolites generated by cancer cells influence the metastatic cascade, encompassing epithelial-mesenchymal transition (EMT), survival of cancer cells in circulation, and metastatic colonization at distant sites. A variety of molecular mechanisms underlie the prometastatic effect of tumor-derived metabolites, such as epigenetic deregulation, induction of matrix metalloproteinases (MMPs), promotion of cancer stemness, and alleviation of oxidative stress. Conversely, metastatic signaling regulates expression and activity of rate-limiting metabolic enzymes to generate prometastatic metabolites thereby reinforcing the metastasis cascade. Understanding the complex interplay between metabolism and metastasis could unravel novel molecular targets, whose intervention could lead to improvements in the treatment of cancer. In this review, we summarized the recent discoveries involving metabolism and tumor metastasis, and emphasized the promising molecular targets, with an update on the development of small molecule or biologic inhibitors against these aberrant situations in cancer.
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Affiliation(s)
- Qinyao Wei
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, Chinese University of Hong Kong, Hong Kong, China
| | - Yun Qian
- Department of Gastroenterology and Hepatology, Shenzhen University General Hospital, Shenzhen, China
| | - Jun Yu
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, Chinese University of Hong Kong, Hong Kong, China
| | - Chi Chun Wong
- Institute of Digestive Disease and Department of Medicine and Therapeutics, State Key Laboratory of Digestive Disease, Li Ka Shing Institute of Health Sciences, CUHK Shenzhen Research Institute, Chinese University of Hong Kong, Hong Kong, China.
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Song WY, Jiang XH, Ding Y, Wang Y, Zhou MX, Xia Y, Zhang CY, Yin CC, Qiu C, Li K, Sun P, Han X. Inhibition of heparanase protects against pancreatic beta cell death in streptozotocin-induced diabetic mice via reducing intra-islet inflammatory cell infiltration. Br J Pharmacol 2020; 177:4433-4447. [PMID: 32608014 DOI: 10.1111/bph.15183] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Revised: 06/18/2020] [Accepted: 06/22/2020] [Indexed: 11/30/2022] Open
Abstract
BACKGROUND AND PURPOSE Intra-islet heparan sulfate (HS) plays an important role in the maintenance of pancreatic islet function. The aim of this study was to investigate the effect mechanism of HS loss on the functioning of islets in diabetic mice. EXPERIMENTAL APPROACH The hypoglycaemic effect of a heparanase inhibitor, OGT2115, was tested in a streptozotocin-induced diabetic mouse model. The islets in pancreatic sections were also stained to reveal their morphology. An insulinoma cell line (MIN6) and primary isolated murine islets were used to investigate the effect of OGT2115 in vitro. KEY RESULTS Intra-islet HS was clearly lost in streptozotocin-induced diabetic mice due to the increased heparanase expression in damaged islets. OGT2115 prevented intra-islet HS loss and improved the glucose profile and insulin secretion in streptozotocin-treated mice. The apoptosis of pancreatic beta cells and the infiltration of mononuclear macrophages, CD4- and CD8-positive T-cells in islets was reduced by OGT2115 in streptozotocin-treated mice, but OGT2115 did not alter the direct streptozotocin-induced damage in vitro. The expression of heparanase was increased in high glucose-treated isolated islets but not in response to direct streptozotocin stimulation. Further experiments showed that high glucose stimuli could decreased expression of PPARγ in cultured islets, thereby relieving the PPARγ-induced inhibition of heparanase gene expression. CONCLUSION AND IMPLICATIONS Hyperglycaemia could cause intra-islet HS loss by elevating the expression of heparanase, thereby aggravating inflammatory cell infiltration and islet damage. Inhibition of heparanase might provide benefit for pancreatic beta cell protection in Type 1 diabetes.
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Affiliation(s)
- Wen-Yu Song
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China
| | - Xiao-Han Jiang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China
| | - Ying Ding
- Department of Pathology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yan Wang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China
| | - Ming-Xuan Zhou
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China
| | - Yun Xia
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China
| | - Chen-Yu Zhang
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China
| | - Chong-Chong Yin
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China
| | - Chen Qiu
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China
| | - Kai Li
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China
| | - Peng Sun
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China
| | - Xiao Han
- Key Laboratory of Human Functional Genomics of Jiangsu Province, Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing, China
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Afaloniati H, Angelopoulou K, Giakoustidis A, Hardas A, Pseftogas A, Makedou K, Gargavanis A, Goulopoulos T, Iliadis S, Papadopoulos V, Papalois A, Mosialos G, Poutahidis T, Giakoustidis D. HDAC1/2 Inhibitor Romidepsin Suppresses DEN-Induced Hepatocellular Carcinogenesis in Mice. Onco Targets Ther 2020; 13:5575-5588. [PMID: 32606772 PMCID: PMC7304783 DOI: 10.2147/ott.s250233] [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: 02/17/2020] [Accepted: 05/27/2020] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a frequently diagnosed cancer and a leading cause of cancer-related death worldwide. Its rapid progression, combined with the limited treatment options at late stages, imposes the need for early detection and aggressive intervention. Based on the knowledge that hepatocarcinogenesis is significantly influenced by histone acetylation, we directed our search for novel HCC therapeutics among histone deacetylation inhibitors (HDACi). The aim of the present study was to investigate the effect of HDAC1/2 inhibitor Romidepsin in the well-established mouse model of diethylnitrosamine (DEN)-induced HCC. MATERIALS AND METHODS C56BL/6 mice were treated with Romidepsin at the critical point of 10 months after DEN challenge and their livers were examined 2 months later using histopathology and morphometry. Protein levels were assessed in serum using ELISA and in liver tissues using Western blot and immunohistochemistry (in-situ detection). Gene expression was quantified using real-time PCR. RESULTS Romidepsin suppressed cancer progression. This effect was associated with decreased proliferation and increased apoptosis of cancer cells. The cell cycle regulator CK2a, the anti-inflammatory molecule PPAR-γ, and the tumor suppressors PTEN and CYLD were upregulated in treated HCC. By contrast, the expression of PI3K, NF-κB p65 and c-Jun was reduced. In line with this result, the levels of two major apoptosis regulators, ie, BAD and the multifunctional protein c-Met, were lower in the blood serum of treated mice compared to the untreated mice with HCC. CONCLUSION These findings suggest that Romidepsin, a drug currently used in the treatment of lymphoma, could also be considered in the management of early-stage HCC.
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Affiliation(s)
- Hara Afaloniati
- Laboratory of Biochemistry and Toxicology, School of Veterinary Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Katerina Angelopoulou
- Laboratory of Biochemistry and Toxicology, School of Veterinary Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Alexander Giakoustidis
- First Department of Surgery, Medical School, Aristotle University of Thessaloniki, General Hospital Papageorgiou, Thessaloniki, Greece
| | - Alexandros Hardas
- Laboratory of Pathology, School of Veterinary Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Athanasios Pseftogas
- School of Biology, Faculty of Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Kali Makedou
- Department of Biological Chemistry, Medical School, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Athanasios Gargavanis
- First Department of Surgery, Medical School, Aristotle University of Thessaloniki, General Hospital Papageorgiou, Thessaloniki, Greece
| | - Thomas Goulopoulos
- First Department of Surgery, Medical School, Aristotle University of Thessaloniki, General Hospital Papageorgiou, Thessaloniki, Greece
| | - Stavros Iliadis
- Department of Biological Chemistry, Medical School, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Vasileios Papadopoulos
- First Department of Surgery, Medical School, Aristotle University of Thessaloniki, General Hospital Papageorgiou, Thessaloniki, Greece
| | - Apostolos Papalois
- Experimental, Educational and Research Center, ELPEN, Pikermi, Attica, Greece
| | - George Mosialos
- School of Biology, Faculty of Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Theofilos Poutahidis
- Laboratory of Pathology, School of Veterinary Medicine, Faculty of Health Sciences, Aristotle University of Thessaloniki, Thessaloniki, Greece
| | - Dimitrios Giakoustidis
- First Department of Surgery, Medical School, Aristotle University of Thessaloniki, General Hospital Papageorgiou, Thessaloniki, Greece
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Zhou H, Xiong Y, Peng L, Wang R, Zhang H, Fu Z. LncRNA-cCSC1 modulates cancer stem cell properties in colorectal cancer via activation of the Hedgehog signaling pathway. J Cell Biochem 2019; 121:2510-2524. [PMID: 31680315 DOI: 10.1002/jcb.29473] [Citation(s) in RCA: 52] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2019] [Accepted: 10/10/2019] [Indexed: 12/27/2022]
Abstract
Several long noncoding RNAs (lncRNAs) have been identified in various malignant tumors and determined to contribute to the process of tumorigenesis, including that of colorectal cancer (CRC). Cancer stem cells (CSCs) have been demonstrated to promote the expansion and maintain the invasion and metastasis of cancer cells, owing to their self-renewal capacity. However, the underlying modulation mechanism of CSC-associated lncRNAs in CRC remains largely unclear. Using integrated bioinformatic analysis, we identified a novel lncRNA (lncRNA-cCSC1) that is highly expressed in CRC and colorectal cancer stem cells (CRCSCs). The biological functions of lncRNA-cCSC1 were assessed in vitro and vivo through the silencing or upregulation of its expression. The depletion of lncRNA-cCSC1 markedly inhibited the self-renewal capacity of the CRCSCs and reduced their drug resistance to 5-fluorouracil. In contrast, lncRNA-cCSC1 overexpression increased the self-renewal effect. Furthermore, aberrant lncRNA-cCSC1 expression resulted in a concomitant alteration of smoothened (SMO) and GLI family zinc finger 1 (Gli1) expression in the Hedgehog (Hh) signaling pathway. Our study is the first to identify a novel lncRNA-cCSC1 in CRC and to indicate that it may regulate CSC-like properties via the Hh signaling pathway. Thus, lncRNA-cCSC1 could be a potential biomarker and promising therapeutic target for CRC.
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Affiliation(s)
- He Zhou
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Yongfu Xiong
- The First Department of Hepatobiliary Surgery, The Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan, China
| | - Linglong Peng
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Rong Wang
- Department of Gastrointestinal Surgery, The Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, China
| | - Hairong Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
| | - Zhongxue Fu
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China
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Zou Y, Watters A, Cheng N, Perry CE, Xu K, Alicea GM, Parris JLD, Baraban E, Ray P, Nayak A, Xu X, Herlyn M, Murphy ME, Weeraratna AT, Schug ZT, Chen Q. Polyunsaturated Fatty Acids from Astrocytes Activate PPARγ Signaling in Cancer Cells to Promote Brain Metastasis. Cancer Discov 2019; 9:1720-1735. [PMID: 31578185 DOI: 10.1158/2159-8290.cd-19-0270] [Citation(s) in RCA: 112] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 08/19/2019] [Accepted: 09/27/2019] [Indexed: 01/21/2023]
Abstract
Brain metastasis, the most lethal form of melanoma and carcinoma, is the consequence of favorable interactions between the invading cancer cells and the brain cells. Peroxisome proliferator-activated receptor γ (PPARγ) has ambiguous functions in cancer development, and its relevance in advanced brain metastasis remains unclear. Here, we demonstrate that astrocytes, the unique brain glial cells, activate PPARγ in brain metastatic cancer cells. PPARγ activation enhances cell proliferation and metastatic outgrowth in the brain. Mechanistically, astrocytes have a high content of polyunsaturated fatty acids that act as "donors" of PPARγ activators to the invading cancer cells. In clinical samples, PPARγ signaling is significantly higher in brain metastatic lesions. Notably, systemic administration of PPARγ antagonists significantly reduces brain metastatic burden in vivo. Our study clarifies a prometastatic role for PPARγ signaling in cancer metastasis in the lipid-rich brain microenvironment and argues for the use of PPARγ blockade to treat brain metastasis. SIGNIFICANCE: Brain-tropic cancer cells take advantage of the lipid-rich brain microenvironment to facilitate their proliferation by activating PPARγ signaling. This protumor effect of PPARγ in advanced brain metastases is in contrast to its antitumor function in carcinogenesis and early metastatic steps, indicating that PPARγ has diverse functions at different stages of cancer development.This article is highlighted in the In This Issue feature, p. 1631.
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Affiliation(s)
- Yongkang Zou
- Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Andrea Watters
- Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Nan Cheng
- Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Caroline E Perry
- Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Ke Xu
- MD/PhD Program, Boston University School of Medicine, Boston, Massachusetts
| | - Gretchen M Alicea
- Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Joshua L D Parris
- Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Ezra Baraban
- Departments of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Pulak Ray
- Delaware Neurosurgical Group, ChristianaCare Health System, Newark, Delaware
| | - Anupma Nayak
- Departments of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Xiaowei Xu
- Departments of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Meenhard Herlyn
- Melanoma Research Center, The Wistar Institute, Philadelphia, Pennsylvania.,Melanoma Research Center, The Wistar Institute, Philadelphia, Pennsylvania
| | - Maureen E Murphy
- Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Ashani T Weeraratna
- Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Zachary T Schug
- Molecular and Cellular Oncogenesis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Qing Chen
- Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
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Dong Z, Chen Y, Yang C, Zhang M, Chen A, Yang J, Huang Y. STAT gene family mRNA expression and prognostic value in hepatocellular carcinoma. Onco Targets Ther 2019; 12:7175-7191. [PMID: 31564902 PMCID: PMC6731967 DOI: 10.2147/ott.s202122] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2019] [Accepted: 08/14/2019] [Indexed: 12/11/2022] Open
Abstract
Background Signal transducer and activator of transcription (STAT) proteins are well-known transcription factors that play an important role in the progression of cancer. However, the association between STAT family genes and hepatocellular carcinoma (HCC) remains unclear. This study investigates the expression level, the prognostic value and the potential mechanism of STAT family genes in HCC. Methods Data from 365 HCC patients in The Cancer Genome Atlas (TCGA) database and 241 HCC patients in the Gene Expression Omnibus (GEO) database were used to investigate the diagnostic and prognostic values of STAT genes by survival analysis and nomogram. Gene set enrichment analysis (GSEA) was used to investigate the potential mechanism of the STAT genes in the development of HCC. Results Our results showed that STAT4/5B mRNA expression levels in HCC tissues were lower than those in normal tissues. Importantly, our results indicated that high expression of STAT5A, STAT5B and STAT6 was associated with better overall survival in HCC patients. Joint effects analysis of STAT5A, STAT5B and STAT6 suggested that the prognosis difference for any combination of genes was more significant than that for any individual gene. Then, we developed a risk score model could predict HCC prognosis and the nomogram visualized gene expression and clinical factors of probability for HCC prognosis. The ROC and calibration curves showed good performance in survival prediction in both the TCGA and the GEO databases. GSEA suggested that high expression of STAT5A, STAT5B and STAT6 were involved in immune-related biological processes, drug metabolism cytochrome P450, JAK-STAT signalling pathway, and PPAR signalling pathways. Conclusion Our data suggest that STAT5A, STAT5B and STAT6 expression may be potential prognostic markers of HCC and, in combination, have a better predictive value for HCC prognosis.
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Affiliation(s)
- Zhitao Dong
- Department of Special Treatment, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, People's Republic of China
| | - Yi Chen
- Department of Hepatobiliary Surgery, Shanghai Public Health Clinical Center, Fudan University, Shanghai 200083, People's Republic of China
| | - Cheng Yang
- Department of Special Treatment, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, People's Republic of China
| | - Meng Zhang
- Department of Hepatobiliary Surgery, Shanghai Public Health Clinical Center, Fudan University, Shanghai 200083, People's Republic of China
| | - Aixue Chen
- Department of Hepatobiliary Surgery, Shanghai Public Health Clinical Center, Fudan University, Shanghai 200083, People's Republic of China
| | - Jiamei Yang
- Department of Special Treatment, Shanghai Eastern Hepatobiliary Surgery Hospital, Shanghai, 200438, People's Republic of China
| | - Yangqing Huang
- Department of Hepatobiliary Surgery, Shanghai Public Health Clinical Center, Fudan University, Shanghai 200083, People's Republic of China
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TNBG-5602, a novel derivative of quinoxaline, inhibits liver cancer growth via upregulating peroxisome proliferator-activated receptor γ in vitro and in vivo. J Pharm Pharmacol 2019; 71:1684-1694. [DOI: 10.1111/jphp.13159] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Accepted: 07/28/2019] [Indexed: 12/30/2022]
Abstract
Abstract
Objectives
TNBG-5602 is a newly synthesized compound with an isoquinoline structure. In the present study, we demonstrated the anticancer effect of TNBG-5602 in in-vitro and in-vivo models and investigated its possible anticancer mechanism.
Methods
The antiproliferation effect of TNBG-5602 in vitro was evaluated in human liver cancer cell line QGY-7701. The acute toxicity of TNBG-5602 was evaluated in mice. The anticancer activity of TNBG-5602 in vivo was assessed in a xenograft model of human liver cancer cell line QGY-7701.
Key findings
The results of CCK-8 assay showed that TNBG-5602 can effectively inhibit the proliferation of liver cancer cells in vitro. The acute toxicity test in mice showed that the LD50 of TNBG-5602 was 172 mg/kg. In a xenograft liver cancer model, TNBG-5602 could remarkably inhibit the growth of tumours. During in-vitro and in-vivo studies, we noted that TNBG-5602 could induce lipid accumulation in cancer cells and tissues. Further study indicated that the anticancer effect of TNBG-5602 may be exerted through activating peroxisome proliferator-activated receptor γ (PPARγ) and downregulating proliferating cell nuclear antigen (PCNA).
Conclusions
Our results suggested that TNBG-5602 might exert potent anticancer activity through increasing the expression of PPARγ.
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Kim YB, Ahn YH, Jung JH, Lee YJ, Lee JH, Kang JL. Programming of macrophages by UV-irradiated apoptotic cancer cells inhibits cancer progression and lung metastasis. Cell Mol Immunol 2019; 16:851-867. [PMID: 30842627 PMCID: PMC6828747 DOI: 10.1038/s41423-019-0209-1] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2018] [Accepted: 02/02/2019] [Indexed: 12/13/2022] Open
Abstract
Apoptotic cell clearance by phagocytes is essential in tissue homeostasis. We demonstrated that conditioned medium (CM) from macrophages exposed to apoptotic cancer cells inhibits the TGFβ1-induced epithelial–mesenchymal transition (EMT), migration, and invasion of cancer cells. Apoptotic 344SQ (ApoSQ) cell-induced PPARγ activity in macrophages increased the levels of PTEN, which was secreted in exosomes. Exosomal PTEN was taken up by recipient lung cancer cells. ApoSQ-exposed CM from PTEN knockdown cells failed to enhance PTEN in 344SQ cells, restore cellular polarity, or exert anti-EMT and anti-invasive effects. The CM that was deficient in PPARγ ligands, including 15-HETE, lipoxin A4, and 15d-PGJ2, could not reverse the suppression of PPARγ activity or the PTEN increase in 344SQ cells and consequently failed to prevent the EMT process. Moreover, a single injection of ApoSQ cells inhibited lung metastasis in syngeneic immunocompetent mice with enhanced PPARγ/PTEN signaling both in tumor-associated macrophages and in tumor cells. PPARγ antagonist GW9662 reversed the signaling by PPARγ/PTEN; the reduction in EMT-activating transcription factors, such as Snai1 and Zeb1; and the antimetastatic effect of the ApoSQ injection. Thus, the injection of apoptotic lung cancer cells may offer a new strategy for the prevention of lung metastasis.
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Affiliation(s)
- Yong-Bae Kim
- Tissue Injury Defense Research Center, College of Medicine, Ewha Womans University, Seoul, 07804, Korea
| | - Young-Ho Ahn
- Tissue Injury Defense Research Center, College of Medicine, Ewha Womans University, Seoul, 07804, Korea.,Department of Molecular Medicine, College of Medicine, Ewha Womans University, Seoul, 07804, Korea
| | - Ji-Hae Jung
- Tissue Injury Defense Research Center, College of Medicine, Ewha Womans University, Seoul, 07804, Korea.,Department of Physiology, College of Medicine, Ewha Womans University, Seoul, 07804, Korea
| | - Ye-Ji Lee
- Tissue Injury Defense Research Center, College of Medicine, Ewha Womans University, Seoul, 07804, Korea.,Department of Physiology, College of Medicine, Ewha Womans University, Seoul, 07804, Korea
| | - Jin-Hwa Lee
- Tissue Injury Defense Research Center, College of Medicine, Ewha Womans University, Seoul, 07804, Korea.,Department of Internal Medicine, College of Medicine, Ewha Womans University, Seoul, 07804, Korea
| | - Jihee Lee Kang
- Tissue Injury Defense Research Center, College of Medicine, Ewha Womans University, Seoul, 07804, Korea. .,Department of Physiology, College of Medicine, Ewha Womans University, Seoul, 07804, Korea.
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Dai B, Ma Y, Yang T, Fan M, Yu R, Su Q, Wang H, Liu F, Yang C, Zhang Y. Synergistic effect of berberine and HMQ1611 impairs cell proliferation and migration by regulating Wnt signaling pathway in hepatocellular carcinoma. Phytother Res 2018; 33:745-755. [PMID: 30565332 DOI: 10.1002/ptr.6267] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2018] [Revised: 11/30/2018] [Accepted: 12/01/2018] [Indexed: 12/13/2022]
Abstract
Hepatocellular carcinoma (HCC) is a biologically complex disease. Combination chemotherapy is a good strategy after surgery treatment. In this study, we report that berberine combined with HMQ1611 (BCH) had a good synergistic effect on the HCC. Our findings concluded that BCH showed good inhibition on the HCC proliferation and colony formation, which attributed to cell cycle arrest by BCH at G1 phase through impairing the expression of cyclinD1, cyclinE, and cdc2 and downregulated the phosphorylation of Akt, mTOR, and ERK. Moreover, BCH negatively regulated Wnt signaling pathway by upregulating the Axin and inhibiting the nuclear translocation of β-catenin. BCH suppressed the phosphorylation of LRP5/6, GSK3β, the expression of Wnt5a, Frizzled8, CK1, and APC, as well as the nucleus protein included MMP2, MMP3, MMP9, and c-myc. The above data of Wnt signaling regulators contributed to inhibition by BCH on cell migration. In vivo studies, BCH significantly suppressed the growth of SMMC-7721 xenograft tumors through downregulating Ki67 and β-catenin, as well as upregulating Axin and p-β-catenin. In conclusion, the results revealed that BCH exhibited potential antitumor activities against human liver cancer in vitro and in vivo, and the potential mechanism underlying these activities depended on the inhibition of the Wnt/β-catenin signaling pathway.
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Affiliation(s)
- Bingling Dai
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, China.,State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an, China
| | - Yujiao Ma
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, China.,State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an, China
| | - Tianfeng Yang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, China.,State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an, China
| | - Mengying Fan
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, China.,State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an, China
| | - Runze Yu
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, China.,State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an, China
| | - Qi Su
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, China.,State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an, China
| | - Hongying Wang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, China.,State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an, China
| | - Feng Liu
- Shaanxi Institute of International Trade & Commence, Xianyang, China
| | - Changhua Yang
- Shaanxi Institute of International Trade & Commence, Xianyang, China
| | - Yanmin Zhang
- School of Pharmacy, Health Science Center, Xi'an Jiaotong University, Xi'an, China.,State Key Laboratory of Shaanxi for Natural Medicines Research and Engineering, Xi'an, China
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Bojková B, Kubatka P, Qaradakhi T, Zulli A, Kajo K. Melatonin May Increase Anticancer Potential of Pleiotropic Drugs. Int J Mol Sci 2018; 19:E3910. [PMID: 30563247 PMCID: PMC6320927 DOI: 10.3390/ijms19123910] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2018] [Revised: 11/27/2018] [Accepted: 12/03/2018] [Indexed: 12/14/2022] Open
Abstract
Melatonin (N-acetyl-5-methoxytryptamine) is not only a pineal hormone, but also an ubiquitary molecule present in plants and part of our diet. Numerous preclinical and some clinical reports pointed to its multiple beneficial effects including oncostatic properties, and as such, it has become one of the most aspiring goals in cancer prevention/therapy. A link between cancer and inflammation and/or metabolic disorders has been well established and the therapy of these conditions with so-called pleiotropic drugs, which include non-steroidal anti-inflammatory drugs, statins and peroral antidiabetics, modulates a cancer risk too. Adjuvant therapy with melatonin may improve the oncostatic potential of these drugs. Results from preclinical studies are limited though support this hypothesis, which, however, remains to be verified by further research.
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Affiliation(s)
- Bianka Bojková
- Department of Animal Physiology, Institute of Biology and Ecology, Faculty of Science, Pavol Jozef Šafárik University in Košice, Šrobárová 2, 041 54 Košice, Slovak Republic.
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, Malá Hora 4, 036 01 Martin, Slovak Republic.
- Department of Experimental Carcinogenesis, Division of Oncology, Biomedical Center Martin, Jessenius Faculty of Medicine, Comenius University in Bratislava, Malá Hora 4C, 036 01 Martin, Slovak Republic.
| | - Tawar Qaradakhi
- Institute for Health and Sport (IHES), Victoria University, Melbourne, VIC 3011, Australia.
| | - Anthony Zulli
- Institute for Health and Sport (IHES), Victoria University, Melbourne, VIC 3011, Australia.
| | - Karol Kajo
- St. Elisabeth Oncology Institute, Heydukova 10, 811 08 Bratislava, Slovak Republic.
- Biomedical Research Center, Slovak Academy of Sciences, Dúbravská cesta 9, 845 05 Bratislava, Slovak Republic.
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Vega-Benedetti AF, Saucedo CN, Zavattari P, Vanni R, Royo F, Llavero F, Zugaza JL, Parada LA. PLAGL1 gene function during hepatoma cells proliferation. Oncotarget 2018; 9:32775-32794. [PMID: 30214684 PMCID: PMC6132347 DOI: 10.18632/oncotarget.25996] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2018] [Accepted: 07/31/2018] [Indexed: 01/15/2023] Open
Abstract
Hepatocellular carcinoma develops as a multistep process, in which cell cycle deregulation is a central feature, resulting in unscheduled proliferation. The PLAGL1 gene encodes a homonym zinc finger protein that is involved in cell-proliferation control. We determined the genomic profile and the transcription and expression level of PLAGL1, simultaneously with that of its molecular partners p53, PPARγ and p21, in cell-lines derived from patients with liver cancer, during in vitro cell growth. Our investigations revealed that genomic and epigenetic changes of PLAGL1 are also present in hepatoma cell-lines. Transcription of PLAGL1 in tumor cells is significantly lower than in normal fibroblasts, but no significant differences in terms of protein expression were detected between these two cell-types, indicating that there is not a direct relationship between the gene transcriptional activity and protein expression. RT-PCR analyses on normal fibroblasts, used as control, also showed that PLAGL1 and p53 genes transcription occurs as an apparent orchestrated process during normal cells proliferation, which gets disturbed in cancer cells. Furthermore, abnormal trafficking of the PLAGL1 protein may occur in hepatocarcinogenesis.
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Affiliation(s)
| | | | - Patrizia Zavattari
- Biochemistry, Biology and Genetics Unit, Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato SP 8, Monserrato, Cagliari, Italy
| | - Roberta Vanni
- Biochemistry, Biology and Genetics Unit, Department of Biomedical Sciences, University of Cagliari, Cittadella Universitaria di Monserrato SP 8, Monserrato, Cagliari, Italy
| | - Felix Royo
- CIC BioGUNE-CIBERehd, Bizkaia Technology Park, Derio, Spain
| | - Francisco Llavero
- Achucarro Basque Center for Neuroscience, UPV/EHU Technology Park, Leioa, Spain.,Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Medicine and Dentistry, University of the Basque Country, Leioa, Spain.,IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - José L Zugaza
- Achucarro Basque Center for Neuroscience, UPV/EHU Technology Park, Leioa, Spain.,Department of Genetics, Physical Anthropology and Animal Physiology, Faculty of Medicine and Dentistry, University of the Basque Country, Leioa, Spain.,IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
| | - Luis A Parada
- Institute of Experimental Pathology, CONICET-UNSa, Salta, Argentina
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Chang SN, Lee JM, Oh H, Kim U, Ryu B, Park JH. Troglitazone inhibits the migration and invasion of PC-3 human prostate cancer cells by upregulating E-cadherin and glutathione peroxidase 3. Oncol Lett 2018; 16:5482-5488. [PMID: 30250621 DOI: 10.3892/ol.2018.9278] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Accepted: 04/28/2017] [Indexed: 11/06/2022] Open
Abstract
Troglitazone (TGZ) is a synthetic peroxisome proliferator-activated receptor γ (PPARγ) ligand that exhibits potential antitumor effects on a number of cancer subtypes, including prostate cancer. However, little is known about the effect of TGZ on metastasis in prostate cancer. The aim of the present study was to determine the inhibitory effect and mechanism underlying TGZ on cell growth, migration and invasion using the prostate cancer PC-3 cell line. Cellular migration and invasion were evaluated by performing a wound healing assay and Matrigel assay, respectively. The expression levels of mRNA and protein were determined by reverse transcription-quantitative polymerase chain reaction and western blotting. The results demonstrated that TGZ dose-dependently inhibited cell migration and invasion of PC-3 cells. The present study also revealed that TGZ increased the mRNA and protein levels of E-cadherin and glutathione peroxidase 3 (GPx3) in human prostate cancer PC-3 cells. In addition, GW9662, a PPARγ antagonist, attenuated the increased mRNA and protein levels of E-cadherin and GPx3, suggesting that the PPARγ-dependent signaling pathway was involved. Taken together, these results suggested that the anti-migration and anti-invasion effect of TGZ on PC-3 prostate cancer cells is, at least in part, mediated via upregulation of E-cadherin and GPx3. The present study also concluded that PPARγ may be used as a potential remedial target for the prevention and treatment of prostate cancer cell invasion and metastasis.
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Affiliation(s)
- Seo-Na Chang
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea
| | - Ji Min Lee
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea
| | - Hanseul Oh
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea
| | - Ukjin Kim
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea
| | - Bokyeong Ryu
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea
| | - Jae-Hak Park
- Department of Laboratory Animal Medicine, College of Veterinary Medicine, Seoul National University, Seoul 151-742, Republic of Korea
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Zhang Y, Wang J, Wu D, Li M, Zhao F, Ren M, Cai Y, Dou J. IL-21-secreting hUCMSCs combined with miR-200c inhibit tumor growth and metastasis via repression of Wnt/β-catenin signaling and epithelial-mesenchymal transition in epithelial ovarian cancer. Onco Targets Ther 2018; 11:2037-2050. [PMID: 29692616 PMCID: PMC5901132 DOI: 10.2147/ott.s147855] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Background Epithelial ovarian cancer (EOC) with insidious characteristic manifests no symptoms in its early onset but most patients have advanced and distant cancer metastasis at diagnosis. Innovative early diagnosis and effective treatment of EOC are urgently needed. Methods In the study, we developed a novel agent of IL-21-secreting human umbilical cord mesenchymal stem cells (hUCMSCs) combined with miR-200c to evaluate its effects on SKOV3 EOC in vitro and in vivo. Results hUCMSCs-LV-IL-21 combined with miR-200c significantly inhibited the SKOV3 cell mobility and tumorigenesis compared with hUCMSCs-LV-IL-21, hUCMSCs-LV-vector, and hUCMSCs, respectively. These were reflected in decreasing the tumor sizes and elongating the tumor bearing nude mouse survival, accompanied with increasing the serum cytokine levels of IFN-γ, IL-21 and TNF-α as well as the splenocyte cytotoxicity. In addition, the expression of β-catenin, cyclin-D1, Gli1, Gli2, and ZEB1 was decreased but the E-cadherin expression was increased in tumor tissues of mice treated with hUCMSCs-LV-IL-21 plus miR-200c. Conclusion We demonstrated that the synergistic effect of fighting SKOV3 EOC is attributable to repression of Wnt/β-catenin signaling and epithelial-mesenchymal transition in SKOV3 EOC. The findings may provide a new strategy for therapy of EOC.
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Affiliation(s)
- Yunxia Zhang
- Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, Nanjing, People's Republic of China.,Department of Gynecology & Obstetrics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Jing Wang
- Department of Gynecology & Obstetrics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Di Wu
- Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Miao Li
- Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Fenshu Zhao
- Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Mulan Ren
- Department of Gynecology & Obstetrics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Yunlong Cai
- Department of Gynecology & Obstetrics, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, People's Republic of China
| | - Jun Dou
- Department of Pathogenic Biology and Immunology, School of Medicine, Southeast University, Nanjing, People's Republic of China
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Prabakaran AD, Karakkat JV, Vijayan R, Chalissery J, Ibrahim MF, Kaimala S, Adeghate EA, Al-Marzouqi AH, Ansari SA, Mensah-Brown E, Emerald BS. Identification of early indicators of altered metabolism in normal development using a rodent model system. Dis Model Mech 2018; 11:dmm.031815. [PMID: 29434026 PMCID: PMC5897726 DOI: 10.1242/dmm.031815] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2017] [Accepted: 01/15/2018] [Indexed: 11/20/2022] Open
Abstract
Although the existence of a close relationship between the early maternal developmental environment, fetal size at birth and the risk of developing disease in adulthood has been suggested, most studies, however, employed experimentally induced intrauterine growth restriction as a model to link this with later adult disease. Because embryonic size variation also occurs under normal growth and differentiation, elucidating the molecular mechanisms underlying these changes and their relevance to later adult disease risk becomes important. The birth weight of rat pups vary according to the uterine horn positions. Using birth weight as a marker, we compared two groups of rat pups – lower birth weight (LBW, 5th to 25th percentile) and average birth weight (ABW, 50th to 75th percentile) – using morphological, biochemical and molecular biology, and genetic techniques. Our results show that insulin metabolism, Pi3k/Akt and Pparγ signaling and the genes regulating growth and metabolism are significantly different in these groups. Methylation at the promoter of the InsII (Ins2) gene and DNA methyltransferase 1 in LBW pups are both increased. Additionally, the Dnmt1 repressor complex, which includes Hdac1, Rb (Rb1) and E2f1, was also upregulated in LBW pups. We conclude that the Dnmt1 repressor complex, which regulates the restriction point of the cell cycle, retards the rate at which cells traverse the G1 or G0 phase of the cell cycle in LBW pups, thereby slowing down growth. This regulatory mechanism mediated by Dnmt1 might contribute to the production of small-size pups and altered physiology and pathology in adult life. Summary: This study suggests an important link between the early embryonic environment and later adult physiology and pathology. At least one process by which this might be coordinated is through the regulatory mechanisms mediated by Dnmt1.
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Affiliation(s)
- Ashok Daniel Prabakaran
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, PO Box 17666, Abu Dhabi, UAE
| | - Jimsheena Valiyakath Karakkat
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, PO Box 17666, Abu Dhabi, UAE
| | - Ranjit Vijayan
- Department of Biology, College of Science, United Arab Emirates University, Al Ain, PO Box 17666, Abu Dhabi, UAE
| | - Jisha Chalissery
- Department of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, PO Box 17666, Abu Dhabi, UAE
| | - Marwa F Ibrahim
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, PO Box 17666, Abu Dhabi, UAE
| | - Suneesh Kaimala
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, PO Box 17666, Abu Dhabi, UAE
| | - Ernest A Adeghate
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, PO Box 17666, Abu Dhabi, UAE
| | - Ahmed Hassan Al-Marzouqi
- Department of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, PO Box 17666, Abu Dhabi, UAE.,Department of Basic Medical Sciences, College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai Healthcare City, PO Box 505055, Dubai, UAE
| | - Suraiya Anjum Ansari
- Department of Biochemistry, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, PO Box 17666, Abu Dhabi, UAE
| | - Eric Mensah-Brown
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, PO Box 17666, Abu Dhabi, UAE
| | - Bright Starling Emerald
- Department of Anatomy, College of Medicine and Health Sciences, United Arab Emirates University, Al Ain, PO Box 17666, Abu Dhabi, UAE
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Rovito D, Gionfriddo G, Barone I, Giordano C, Grande F, De Amicis F, Lanzino M, Catalano S, Andò S, Bonofiglio D. Ligand-activated PPARγ downregulates CXCR4 gene expression through a novel identified PPAR response element and inhibits breast cancer progression. Oncotarget 2018; 7:65109-65124. [PMID: 27556298 PMCID: PMC5323141 DOI: 10.18632/oncotarget.11371] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2016] [Accepted: 08/11/2016] [Indexed: 12/26/2022] Open
Abstract
Stromal Derived Factor-1α (SDF-1α) and its cognate receptor CXCR4 play a key role in mediating breast cancer cell invasion and metastasis. Therefore, drugs able to inhibit CXCR4 activation may add critical tools to reduce tumor progression, especially in the most aggressive form of the breast cancer disease. Peroxisome Proliferator-Activated Receptor (PPAR) γ, a member of the nuclear receptor superfamily, has been found to downregulate CXCR4 gene expression in different cancer cells, however the molecular mechanism underlying this effect is not fully understood. Here, we identified a novel PPARγ-mediated mechanism that negatively regulates CXCR4 expression in both epithelial and stromal breast cancer cells. We found that ligand-activated PPARγ downregulated CXCR4 transcriptional activity through the recruitment of the silencing mediator of retinoid and thyroid hormone receptor (SMRT) corepressor onto a newly identified PPAR response element (PPRE) within the CXCR4 promoter in breast cancer cell lines. As a consequence, the PPARγ agonist rosiglitazone (BRL) significantly inhibited cell migration and invasion and this effect was PPARγ-mediated, since it was reversed in the presence of the PPARγ antagonist GW9662. According to the ability of cancer-associated fibroblasts (CAFs), the most abundant component of breast cancer stroma, to secrete high levels of SDF-1α, BRL reduced migratory promoting activities induced by conditioned media (CM) derived from CAFs and affected CXCR4 downstream signaling pathways activated by CAF-CM. In addition, CAFs exposed to BRL showed a decreased expression of CXCR4, a reduced motility and invasion along with a phenotype characterized by an altered morphology. Collectively, our findings provide novel insights into the role of PPARγ in inhibiting breast cancer progression and further highlight the utility of PPARγ ligands for future therapies aimed at targeting both cancer and surrounding stromal cells in breast cancer patients.
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Affiliation(s)
- Daniela Rovito
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.,Centro Sanitario, University of Calabria, Rende (CS), Italy
| | - Giulia Gionfriddo
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy
| | - Ines Barone
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy
| | | | - Fedora Grande
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy
| | - Francesca De Amicis
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy
| | - Marilena Lanzino
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy
| | - Stefania Catalano
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy
| | - Sebastiano Andò
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy.,Centro Sanitario, University of Calabria, Rende (CS), Italy
| | - Daniela Bonofiglio
- Department of Pharmacy, Health and Nutritional Sciences, University of Calabria, Rende (CS), Italy
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50
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Research Advances in the Correlation between Peroxisome Proliferator-Activated Receptor- γ and Digestive Cancers. PPAR Res 2018; 2018:5289859. [PMID: 29483923 PMCID: PMC5816837 DOI: 10.1155/2018/5289859] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2017] [Revised: 10/14/2017] [Accepted: 10/25/2017] [Indexed: 02/07/2023] Open
Abstract
Peroxisome proliferator-activated receptor-γ (PPARγ) is a class of ligand-activated nuclear transcription factors, which is a member of type II nuclear receptor superfamily. Previous studies demonstrate that PPARγ is expressed in a variety of tumor tissues and is closely associated with the proliferation and prognosis of digestive system tumors by its roles in mediation of cell differentiation, induction of cell apoptosis, and inhibition of cell proliferation.
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