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Zhu F, Jiang J, Chen X, Fu L, Liu H, Zhang H. Amentoflavone regulates the miR-124-3p/CAPN2 axis to promote mitochondrial autophagy in HCC cells. Toxicol Res (Camb) 2024; 13:tfae110. [PMID: 39050595 PMCID: PMC11263925 DOI: 10.1093/toxres/tfae110] [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: 12/12/2023] [Revised: 07/04/2024] [Indexed: 07/27/2024] Open
Abstract
BACKGROUND Hepatocellular carcinoma (HCC) is a disease with poor prognosis and high mortality. Amentoflavone (AF) possesses the characteristics of marginal toxicity, stable curative effect, and good anti-HCC activity. This study aimed to evaluate the molecular mechanism of AF inhibiting HCC and provide a new idea for HCC treatment. METHODS Clinical tissue of HCC was collected. AF was given with HCC cells, and transfected with corresponding vectors. MiR-124-3p expression in HCC clinical samples and cells was ascertained by qRT-PCR assay. HCC cells viability was identified by CCK-8 assay. LC3 protein expression was ascertained by immunofluorescence assay. The expressions of CAPN2, β-catenin and mitochondrial autophagy-related proteins were detected by western blot. Dual-luciferase reporter gene assay confirmed the targeting relationship of miR-124-3p and CAPN2. RESULTS MiR-124-3p expression was inhibited and CAPN2 expression was increased in HCC tissues and cells. AF decreased HCC cell viability, up-regulated miR-124-3p expression, and inhibited CAPN2 expression and β-catenin nuclear transcription. Moreover, AF could activate the mitochondrial autophagy of HCC cells. MiR-124-3p specifically regulated CAPN2 expression. This study found that CAPN2 could promote β-catenin nuclear translocation, thus activating wnt/β-catenin pathway to inhibit mitochondrial autophagy in HCC cells. MiR-124-3p mimics enhanced AF function in promoting mitochondrial autophagy in HCC cells. However, CAPN2 overexpression, miR-124-3p inhibitor and SKL2001 attenuated the effectiveness of AF. CONCLUSION This study confirmed that AF regulated miR-124-3p/CAPN2 axis to restraint β-catenin nuclear translocation and then inhibit the wnt/β-catenin pathway, thereby promoting mitochondrial autophagy in HCC.
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Affiliation(s)
- Fengting Zhu
- Department of Oncology, Guangdong Provincial Hospital of Traditional Chinese Medicine Hainan Hospital, No. 13, Shunda Road, Meilan District, Haikou 570203, Hainan Province, P.R. China
| | - Jingwen Jiang
- Department of Oncology, Guangdong Provincial Hospital of Traditional Chinese Medicine Hainan Hospital, No. 13, Shunda Road, Meilan District, Haikou 570203, Hainan Province, P.R. China
| | - Xuewu Chen
- Department of Oncology, Guangdong Provincial Hospital of Traditional Chinese Medicine Hainan Hospital, No. 13, Shunda Road, Meilan District, Haikou 570203, Hainan Province, P.R. China
| | - Lei Fu
- Department of Oncology, Guangdong Provincial Hospital of Traditional Chinese Medicine Hainan Hospital, No. 13, Shunda Road, Meilan District, Haikou 570203, Hainan Province, P.R. China
| | - Hui Liu
- Departments of Interventional Radiology, Central South University, Xiangya School of Medicine Affiliated Haikou Hospital, No. 43, people’s Blvd., Haikou 570208, Hainan Province, P.R. China
| | - Hui Zhang
- Department of Oncology, Guangdong Provincial Hospital of Traditional Chinese Medicine Hainan Hospital, No. 13, Shunda Road, Meilan District, Haikou 570203, Hainan Province, P.R. China
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Singh B, Cui K, Eisa-Beygi S, Zhu B, Cowan DB, Shi J, Wang DZ, Liu Z, Bischoff J, Chen H. Elucidating the crosstalk between endothelial-to-mesenchymal transition (EndoMT) and endothelial autophagy in the pathogenesis of atherosclerosis. Vascul Pharmacol 2024; 155:107368. [PMID: 38548093 PMCID: PMC11303600 DOI: 10.1016/j.vph.2024.107368] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2024] [Revised: 03/07/2024] [Accepted: 03/25/2024] [Indexed: 04/26/2024]
Abstract
Atherosclerosis, a chronic systemic inflammatory condition, is implicated in most cardiovascular ischemic events. The pathophysiology of atherosclerosis involves various cell types and associated processes, including endothelial cell activation, monocyte recruitment, smooth muscle cell migration, involvement of macrophages and foam cells, and instability of the extracellular matrix. The process of endothelial-to-mesenchymal transition (EndoMT) has recently emerged as a pivotal process in mediating vascular inflammation associated with atherosclerosis. This transition occurs gradually, with a significant portion of endothelial cells adopting an intermediate state, characterized by a partial loss of endothelial-specific gene expression and the acquisition of "mesenchymal" traits. Consequently, this shift disrupts endothelial cell junctions, increases vascular permeability, and exacerbates inflammation, creating a self-perpetuating cycle that drives atherosclerotic progression. While endothelial cell dysfunction initiates the development of atherosclerosis, autophagy, a cellular catabolic process designed to safeguard cells by recycling intracellular molecules, is believed to exert a significant role in plaque development. Identifying the pathological mechanisms and molecular mediators of EndoMT underpinning endothelial autophagy, may be of clinical relevance. Here, we offer new insights into the underlying biology of atherosclerosis and present potential molecular mechanisms of atherosclerotic resistance and highlight potential therapeutic targets.
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Affiliation(s)
- Bandana Singh
- Vascular Biology Program, Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Kui Cui
- Vascular Biology Program, Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Shahram Eisa-Beygi
- Vascular Biology Program, Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Bo Zhu
- Vascular Biology Program, Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Douglas B Cowan
- Vascular Biology Program, Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Jinjun Shi
- Department of Anesthesiology, Perioperative and Pain Medicine, Brigham and Women's Hospital, Boston, MA, USA
| | - Da-Zhi Wang
- Center for Regenerative Medicine, University of South Florida Health Heart Institute, Morsani College of Medicine, University of South Florida, Tampa, FL, USA
| | - Zhenguo Liu
- Division of Cardiovascular Medicine, Department of Medicine, University of Missouri School of Medicine, Columbia, MO, USA
| | - Joyce Bischoff
- Vascular Biology Program, Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA
| | - Hong Chen
- Vascular Biology Program, Department of Surgery, Harvard Medical School, Boston Children's Hospital, Boston, MA, USA.
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Jabeen I, Altemimi AB, Rabail R, Kafeel S, Shahid A, Inam-Ur-Raheem M, Mousavi Khaneghah A, Aadil RM. Exploring the astonishing beneficial effects of round gourd (Praecitrullus fistulosus) and plant lectins towards cancer: A comprehensive review. Int J Biol Macromol 2024; 271:132629. [PMID: 38815952 DOI: 10.1016/j.ijbiomac.2024.132629] [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: 03/22/2024] [Revised: 05/20/2024] [Accepted: 05/22/2024] [Indexed: 06/01/2024]
Abstract
Praecitrullus fistulosus, commonly known as round gourd or tinda, is a remarkable source of bioactive substances like polyphenols, antioxidants, carotene, magnesium, and vitamin C. It is considered one of the Cucurbitaceae family due to its medicinal features. Plant lectins are carbohydrate-binding proteins that can bind and identify the carbohydrate moieties upon cancerous cells demonstrated some anticancer potentials. Several plant lectins are helpful as cancer biomarkers because they can find cancer cells and contribute to cell death initiation via apoptosis and autophagy, suggesting the possible role of cancer-inhibiting pathways. Therefore, round gourd and lectins might be useful in the controlling of cancer. This study compiled the most recent scientific literature regarding the round gourd and numerous plant lectins, and the clinical trials of lectins exploring their effects on cancer were examined. Research according to the literature, round gourd, and lectins demonstrated pharmacological alterations not only in cancer but in many other disorders as well. Thus, clinical investigations proved the beneficial impacts of round gourd and lectins on cancer due to their antioxidants, anti-inflammatory, and anticarcinogenic properties. Further studies are required to fully comprehend the potential applications of these plant-derived compounds against cancer, as well as to identify the round gourd components and clarify their mode of action.
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Affiliation(s)
- Ifrah Jabeen
- National Institute of Food Science and Technology, University of Agriculture, Faisalabad 38000, Pakistan
| | - Ammar B Altemimi
- Food Science Department, College of Agriculture, University of Basrah, Basrah 61004, Iraq; College of Medicine, University of Warith Al-Anbiyaa, Karbala 56001, Iraq
| | - Roshina Rabail
- National Institute of Food Science and Technology, University of Agriculture, Faisalabad 38000, Pakistan
| | - Sadia Kafeel
- National Institute of Food Science and Technology, University of Agriculture, Faisalabad 38000, Pakistan
| | - Arashi Shahid
- National Institute of Food Science and Technology, University of Agriculture, Faisalabad 38000, Pakistan
| | - Muhammad Inam-Ur-Raheem
- National Institute of Food Science and Technology, University of Agriculture, Faisalabad 38000, Pakistan.
| | - Amin Mousavi Khaneghah
- Faculty of Biotechnologies (BioTech), ITMO University 191002, 9 Lomonosova Street, Saint Petersburg, Russia; Halal Research Center of IRI, Iran Food and Drug Administration, Ministry of Health and Medical Education, Tehran, Iran.
| | - Rana Muhammad Aadil
- National Institute of Food Science and Technology, University of Agriculture, Faisalabad 38000, Pakistan.
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Choi BM, Cheong JH, Ryu JI, Won YD, Min KW, Han MH. Significant Genes Associated with Mortality and Disease Progression in Grade II and III Glioma. Biomedicines 2024; 12:858. [PMID: 38672212 PMCID: PMC11048596 DOI: 10.3390/biomedicines12040858] [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: 03/25/2024] [Revised: 04/09/2024] [Accepted: 04/11/2024] [Indexed: 04/28/2024] Open
Abstract
BACKGROUND The Wnt/β-catenin pathway plays a critical role in the tumorigenesis and maintenance of glioma stem cells. This study aimed to evaluate significant genes associated with the Wnt/β-catenin pathway involved in mortality and disease progression in patients with grade II and III glioma, using the Cancer Genome Atlas (TCGA) database. METHODS We obtained clinicopathological information and mRNA expression data from 515 patients with grade II and III gliomas from the TCGA database. We performed a multivariate Cox regression analysis to identify genes independently associated with glioma prognosis. RESULTS The analysis of 34 genes involved in Wnt/β-catenin signaling demonstrated that four genes (CER1, FRAT1, FSTL1, and RPSA) related to the Wnt/β-catenin pathway were significantly associated with mortality and disease progression in patients with grade II and III glioma. We also identified additional genes related to the four significant genes of the Wnt/β-catenin pathway mentioned above. The higher expression of BMP2, RPL18A, RPL19, and RPS12 is associated with better outcomes in patients with glioma. CONCLUSIONS Using a large-scale open database, we identified significant genes related to the Wnt/β-catenin signaling pathway associated with mortality and disease progression in patients with grade II and III gliomas.
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Affiliation(s)
- Bo Mi Choi
- Department of Neurosurgery, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri 11923, Gyeonggi-do, Republic of Korea; (B.M.C.); (J.H.C.); (J.I.R.); (Y.D.W.)
| | - Jin Hwan Cheong
- Department of Neurosurgery, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri 11923, Gyeonggi-do, Republic of Korea; (B.M.C.); (J.H.C.); (J.I.R.); (Y.D.W.)
| | - Je Il Ryu
- Department of Neurosurgery, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri 11923, Gyeonggi-do, Republic of Korea; (B.M.C.); (J.H.C.); (J.I.R.); (Y.D.W.)
| | - Yu Deok Won
- Department of Neurosurgery, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri 11923, Gyeonggi-do, Republic of Korea; (B.M.C.); (J.H.C.); (J.I.R.); (Y.D.W.)
| | - Kyueng-Whan Min
- Department of Pathology, Uijeongbu Eulji Medical Center, Eulji University School of Medicine, Uijeongbu 11759, Gyeonggi-do, Republic of Korea
| | - Myung-Hoon Han
- Department of Neurosurgery, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri 11923, Gyeonggi-do, Republic of Korea; (B.M.C.); (J.H.C.); (J.I.R.); (Y.D.W.)
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Davoodvandi A, Rafiyan M, Mansournia MA, Rajabpoor Nikoo N, Saati M, Samimi M, Asemi Z. MicroRNA and gynecological cancers: Focus on miR-195. Pathol Res Pract 2023; 249:154784. [PMID: 37639954 DOI: 10.1016/j.prp.2023.154784] [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: 08/06/2023] [Revised: 08/19/2023] [Accepted: 08/23/2023] [Indexed: 08/31/2023]
Abstract
Different cancer types have been shown to have down-regulated expression levels of miR-195 as an anti-tumor agent. MiR-195 family members can inhibit cancer cell proliferation, angiogenesis, epithelial-mesenchymal transition and metastases, immunosuppression, glycolysis, drug resistance, and cancer stem cell development by targeting the 3'-UTR of the mRNA of different pro-tumor genes. MiR-195 identified as a tumor suppressor miR in a variety of cancers, most notably gynecological malignancies such as cervical, endometrial, and ovarian carcinoma. As a result, restoring miR-195 expression should be regarded as a potential therapy for either prevention or treatment of gynecological cancers. This review will present the most recent data about miR-195-mediated anti-tumor effects in gynecological malignancies, emphasizing its downstream signaling pathways and target genes, as well as prospective treatment techniques.
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Affiliation(s)
- Amirhossein Davoodvandi
- Cancer Immunology Project (CIP), Universal Scientific Education and Research Network (USERN), Tehran, Islamic Republic of Iran; Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran
| | - Mahdi Rafiyan
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran.
| | - Mohammad Ali Mansournia
- Department of Epidemiology and Biostatistics, School of Public Health, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran
| | - Nesa Rajabpoor Nikoo
- Department of Gynecology and Obstetrics, Tehran University of Medical Sciences, Tehran, Islamic Republic of Iran.
| | - Maryam Saati
- Department of Nursing, Semnan Branch, Islamic Azad University, Semnan, Islamic Republic of Iran
| | - Mansooreh Samimi
- Department of Gynecology and Obstetrics, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran.
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Islamic Republic of Iran.
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Salim R, Nehvi IB, Mir RA, Tyagi A, Ali S, Bhat OM. A review on anti-nutritional factors: unraveling the natural gateways to human health. Front Nutr 2023; 10:1215873. [PMID: 37720376 PMCID: PMC10501406 DOI: 10.3389/fnut.2023.1215873] [Citation(s) in RCA: 22] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Accepted: 08/15/2023] [Indexed: 09/19/2023] Open
Abstract
Humans are constantly facing multiple health challenges from both communicable and non-communicable diseases that significantly affect their health. Additionally, drug resistance or failure has made the situation even worse and poses serious challenges for researchers to develop new drugs. Hence, to address these problems, there is an urgent need to discover and develop timely and long-term-based therapeutic treatments from different sources. One such approach is harnessing the potential of plant secondary metabolites. Plants have been utilized for therapeutic purposes in addition to being used for nutritional benefits. In the last two decades, plant-based drug developments have been one of the effective means of treating human diseases owing to their multiple functions. More recently, anti-nutritional factors (ANFs) have emerged as one of the important targets for novel plant-based drug development due to their multifaceted and potential pharmacological properties. However, their anti-nutritional properties have been the major setback for their limited success in the pharmacological sector. In this review, we provide an overview of ANFs and their beneficial roles in preventing human diseases with multiple case studies. We also highlight the recent developments and applications of ANFs in the food industry, agriculture, and pharmaceutics with future perspectives. Furthermore, we evaluate meta-analyses on ANFs from the last 30 years in relation to their function in human health benefits. This review is an endeavor to reevaluate the merit of these natural compounds and explore their potential for both human and animal health.
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Affiliation(s)
- Rehana Salim
- Division of Food Science and Technology, SKUAST, Shalimar, India
| | | | - Rakeeb Ahmad Mir
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, India
| | - Anshika Tyagi
- Department of Biotechnology, Yeungnam University, Gyeongsan, Republic of Korea
| | - Sajad Ali
- Department of Biotechnology, Yeungnam University, Gyeongsan, Republic of Korea
| | - Owais M. Bhat
- Department of Biotechnology, School of Life Sciences, Central University of Kashmir, Ganderbal, India
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Zhang H, Shen S, Feng C, Chen G, Wang X. MFAP2 promotes the progression of oral squamous cell carcinoma by activating the Wnt/β-catenin signaling pathway through autophagy. Acta Biochim Biophys Sin (Shanghai) 2023; 55:1445-1455. [PMID: 37592847 PMCID: PMC10520470 DOI: 10.3724/abbs.2023079] [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: 12/07/2022] [Accepted: 03/23/2023] [Indexed: 08/19/2023] Open
Abstract
Microfibrillar-associated protein 2 (MFAP2) is a small glycoprotein that is involved in vascular development and metabolic disease. The present study aims to explore the regulatory role of MFAP2 in the development and progression of oral squamous cell carcinoma (OSCC), including the underlying mechanisms. MFAP2 expression and its association with the progression of OSCC are explored using bioinformatics. MFAP2 expression in OSCC tissues is detected by immunohistochemical staining. SCC15 cell migration, invasion, apoptosis, proliferation, and viability are detected by wound healing, Transwell, flow cytometry, colony formation, and cell counting kit-8 assays. An in vivo experiment is used to detect tumor formation. Western blot analysis is used to determine MFAP2's regulatory role in autophagy and the Wnt/β-catenin signaling pathway. MFAP2 is highly expressed in SCC15 cells and OSCC tissues, which correlates positively with the poor prognosis of patients with OSCCs. Functionally, MFAP2 promotes oncogenic autophagy to increase cell invasion, migration, and proliferation but inhibits apoptosis in SCC15 cells and promotes tumor growth in vivo. Mechanistically, MFAP2 upregulates autophagy and Wnt/β-catenin signaling to stimulate OSCC development. Intriguingly, regulation of Wnt/β-catenin signaling dependent on autophagy contributes to the malignant behaviors of SCC15 cells. MFAP2 could serve as a novel biomarker for OSCC and could affect OSCC tumorigenesis and development via autophagic regulation of Wnt/β-catenin signaling.
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Affiliation(s)
- Hao Zhang
- Tianjin Institute of Environmental and Operational MedicineTianjin300050China
- School and Hospital of StomatologyTianjin Medical UniversityTianjin300070China
| | - Si Shen
- Tianjin Institute of Environmental and Operational MedicineTianjin300050China
- School and Hospital of StomatologyTianjin Medical UniversityTianjin300070China
| | - Chong Feng
- Tianjin Institute of Environmental and Operational MedicineTianjin300050China
- School and Hospital of StomatologyTianjin Medical UniversityTianjin300070China
| | - Gang Chen
- School and Hospital of StomatologyTianjin Medical UniversityTianjin300070China
| | - Xinxing Wang
- Tianjin Institute of Environmental and Operational MedicineTianjin300050China
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Novoa Díaz MB, Carriere P, Gentili C. How the interplay among the tumor microenvironment and the gut microbiota influences the stemness of colorectal cancer cells. World J Stem Cells 2023; 15:281-301. [PMID: 37342226 PMCID: PMC10277969 DOI: 10.4252/wjsc.v15.i5.281] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/26/2022] [Revised: 03/06/2023] [Accepted: 04/17/2023] [Indexed: 05/26/2023] Open
Abstract
Colorectal cancer (CRC) remains the third most prevalent cancer disease and involves a multi-step process in which intestinal cells acquire malignant characteristics. It is well established that the appearance of distal metastasis in CRC patients is the cause of a poor prognosis and treatment failure. Nevertheless, in the last decades, CRC aggressiveness and progression have been attributed to a specific cell population called CRC stem cells (CCSC) with features like tumor initiation capacity, self-renewal capacity, and acquired multidrug resistance. Emerging data highlight the concept of this cell subtype as a plastic entity that has a dynamic status and can be originated from different types of cells through genetic and epigenetic changes. These alterations are modulated by complex and dynamic crosstalk with environmental factors by paracrine signaling. It is known that in the tumor niche, different cell types, structures, and biomolecules coexist and interact with cancer cells favoring cancer growth and development. Together, these components constitute the tumor microenvironment (TME). Most recently, researchers have also deepened the influence of the complex variety of microorganisms that inhabit the intestinal mucosa, collectively known as gut microbiota, on CRC. Both TME and microorganisms participate in inflammatory processes that can drive the initiation and evolution of CRC. Since in the last decade, crucial advances have been made concerning to the synergistic interaction among the TME and gut microorganisms that condition the identity of CCSC, the data exposed in this review could provide valuable insights into the biology of CRC and the development of new targeted therapies.
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Affiliation(s)
- María Belén Novoa Díaz
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Pedro Carriere
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
| | - Claudia Gentili
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur, Bahía Blanca 8000, Buenos Aires, Argentina
- Instituto de Ciencias Biológicas y Biomédicas del Sur, Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET)- Universidad Nacional del Sur (UNS), Bahía Blanca 8000, Buenos Aires, Argentina
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Kocyigit E, Kocaadam-Bozkurt B, Bozkurt O, Ağagündüz D, Capasso R. Plant Toxic Proteins: Their Biological Activities, Mechanism of Action and Removal Strategies. Toxins (Basel) 2023; 15:356. [PMID: 37368657 PMCID: PMC10303728 DOI: 10.3390/toxins15060356] [Citation(s) in RCA: 25] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2023] [Revised: 05/11/2023] [Accepted: 05/19/2023] [Indexed: 06/29/2023] Open
Abstract
Plants evolve to synthesize various natural metabolites to protect themselves against threats, such as insects, predators, microorganisms, and environmental conditions (such as temperature, pH, humidity, salt, and drought). Plant-derived toxic proteins are often secondary metabolites generated by plants. These proteins, including ribosome-inactivating proteins, lectins, protease inhibitors, α-amylase inhibitors, canatoxin-like proteins and ureases, arcelins, antimicrobial peptides, and pore-forming toxins, are found in different plant parts, such as the roots, tubers, stems, fruits, buds, and foliage. Several investigations have been conducted to explore the potential applications of these plant proteins by analyzing their toxic effects and modes of action. In biomedical applications, such as crop protection, drug development, cancer therapy, and genetic engineering, toxic plant proteins have been utilized as potentially useful instruments due to their biological activities. However, these noxious metabolites can be detrimental to human health and cause problems when consumed in high amounts. This review focuses on different plant toxic proteins, their biological activities, and their mechanisms of action. Furthermore, possible usage and removal strategies for these proteins are discussed.
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Affiliation(s)
- Emine Kocyigit
- Department of Nutrition and Dietetics, Ordu University, Cumhuriyet Yerleşkesi, 52200 Ordu, Turkey;
| | - Betul Kocaadam-Bozkurt
- Department of Nutrition and Dietetics, Erzurum Technical University, Yakutiye, 25100 Erzurum, Turkey; (B.K.-B.); (O.B.)
| | - Osman Bozkurt
- Department of Nutrition and Dietetics, Erzurum Technical University, Yakutiye, 25100 Erzurum, Turkey; (B.K.-B.); (O.B.)
| | - Duygu Ağagündüz
- Department of Nutrition and Dietetics, Gazi University, Faculty of Health Sciences, Emek, 06490 Ankara, Turkey;
| | - Raffaele Capasso
- Department of Agricultural Sciences, University of Naples Federico II, 80055 Portici, Italy
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Duraiswamy A, Sneha A. NM, Jebakani K. S, Selvaraj S, Pramitha J. L, Selvaraj R, Petchiammal K. I, Kather Sheriff S, Thinakaran J, Rathinamoorthy S, Kumar P. R. Genetic manipulation of anti-nutritional factors in major crops for a sustainable diet in future. FRONTIERS IN PLANT SCIENCE 2023; 13:1070398. [PMID: 36874916 PMCID: PMC9976781 DOI: 10.3389/fpls.2022.1070398] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 12/19/2022] [Indexed: 06/18/2023]
Abstract
The consumption of healthy food, in order to strengthen the immune system, is now a major focus of people worldwide and is essential to tackle the emerging pandemic concerns. Moreover, research in this area paves the way for diversification of human diets by incorporating underutilized crops which are highly nutritious and climate-resilient in nature. However, although the consumption of healthy foods increases nutritional uptake, the bioavailability of nutrients and their absorption from foods also play an essential role in curbing malnutrition in developing countries. This has led to a focus on anti-nutrients that interfere with the digestion and absorption of nutrients and proteins from foods. Anti-nutritional factors in crops, such as phytic acid, gossypol, goitrogens, glucosinolates, lectins, oxalic acid, saponins, raffinose, tannins, enzyme inhibitors, alkaloids, β-N-oxalyl amino alanine (BOAA), and hydrogen cyanide (HCN), are synthesized in crop metabolic pathways and are interconnected with other essential growth regulation factors. Hence, breeding with the aim of completely eliminating anti-nutrition factors tends to compromise desirable features such as yield and seed size. However, advanced techniques, such as integrated multi-omics, RNAi, gene editing, and genomics-assisted breeding, aim to breed crops in which negative traits are minimized and to provide new strategies to handle these traits in crop improvement programs. There is also a need to emphasize individual crop-based approaches in upcoming research programs to achieve smart foods with minimum constraints in future. This review focuses on progress in molecular breeding and prospects for additional approaches to improve nutrient bioavailability in major crops.
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Affiliation(s)
- Aishwarya Duraiswamy
- Genetics and Plant Breeding, School of Agricultural Sciences, Karunya Institute of Technology and Sciences, Coimbatore, India
| | - Nancy Mano Sneha A.
- Genetics and Plant Breeding, School of Agricultural Sciences, Karunya Institute of Technology and Sciences, Coimbatore, India
| | - Sherina Jebakani K.
- Genetics and Plant Breeding, School of Agricultural Sciences, Karunya Institute of Technology and Sciences, Coimbatore, India
| | - Sellakumar Selvaraj
- Genetics and Plant Breeding, School of Agricultural Sciences, Karunya Institute of Technology and Sciences, Coimbatore, India
| | - Lydia Pramitha J.
- Genetics and Plant Breeding, School of Agricultural Sciences, Karunya Institute of Technology and Sciences, Coimbatore, India
| | - Ramchander Selvaraj
- Genetics and Plant Breeding, School of Agricultural Sciences, Karunya Institute of Technology and Sciences, Coimbatore, India
| | - Indira Petchiammal K.
- Genetics and Plant Breeding, School of Agricultural Sciences, Karunya Institute of Technology and Sciences, Coimbatore, India
| | - Sharmili Kather Sheriff
- Agronomy, School of Agricultural Sciences, Karunya Institute of Technology and Sciences, Coimbatore, India
| | - Jenita Thinakaran
- Horticulture, School of Agricultural Sciences, Karunya Institute of Technology and Sciences, Coimbatore, India
| | - Samundeswari Rathinamoorthy
- Crop Physiology, School of Agricultural Sciences, Karunya Institute of Technology and Sciences, Coimbatore, India
| | - Ramesh Kumar P.
- Plant Biochemistry, School of Agricultural Sciences, Karunya Institute of Technology and Sciences, Coimbatore, India
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11
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Qian H, Wang L, Li Y, Wang B, Li C, Fang L, Tang L. The traditional uses, phytochemistry and pharmacology of Abrus precatorius L.: A comprehensive review. JOURNAL OF ETHNOPHARMACOLOGY 2022; 296:115463. [PMID: 35714881 DOI: 10.1016/j.jep.2022.115463] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/22/2022] [Revised: 05/30/2022] [Accepted: 06/12/2022] [Indexed: 06/09/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Abrus precatorius L. (AP) is a folk medicine with a long-term medicinal history worldwide, which is extensively applied to various ailments, such as bronchitis, jaundice, hepatitis, contraception, tumor, abortion, malaria, etc. Meanwhile, its leaves are also served as tea in China, and its roots are employed as a substitute for Glycyrrhiza uralensis or as a raw material for the extraction of glycyrrhizin in India. Thus, AP is considered to be a plant with dual values of medicine and economy as well as its chemical composition and biological activity, which are of growing interest to the scientific community. AIM OF REVIEW In the review, the traditional application, botany, chemical constituents, pharmacological activities, and toxicity are comprehensively and systematically summarized. MATERIALS AND METHODS An extensive database retrieval was conducted to gather the specific information about AP from 1871 to 2022 using online bibliographic databases Web of Science, PubMed, SciFinder, Google Scholar, CNKI, and Baidu Scholar. The search terms comprise the keywords "Abrus precatorius", "phytochemistry", "pharmacological activity", "toxicity" and "traditional application" as a combination. RESULTS To date, AP is traditionally used to treat various diseases, including sore throat, cough, bronchitis, jaundice, hepatitis, abdominal pain, contraception, tumor, abortion, malaria, and so on. More than 166 chemical compounds have been identified from AP, which primarily cover flavonoids, phenolics, terpenoids, steroids, alkaloids, organic acids, esters, proteins, polysaccharides, and so on. A wide range of in vitro and in vivo pharmacological functions of AP have been reported, such as antitumor, antimicrobial, insecticidal, antiprotozoal, antiparasitic, anti-inflammatory, antioxidant, immunomodulatory, antifertility, antidiabetic, other pharmacological activities. The crushed seeds in powder or paste form were comparatively toxic to humans and animals by oral administration. Interestingly, the methanolic extracts were non-toxic to adult Wistar albino rats at various doses (200 and 400 mg/kg) daily. CONCLUSIONS The review focuses on the traditional application, botany, phytochemistry, pharmacological activities, and toxicity of AP, which offers a valuable context for researchers on the current research status and a reference for further research and applications of this medicinal plant.
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Affiliation(s)
- Huiqin Qian
- College of Pharmacy, Sanquan College of Xinxiang Medical University, Xinxiang, 453000, China.
| | - Lu Wang
- College of Pharmacy, Sanquan College of Xinxiang Medical University, Xinxiang, 453000, China
| | - Yanling Li
- College of Pharmacy, Sanquan College of Xinxiang Medical University, Xinxiang, 453000, China
| | - Bailing Wang
- College of Pharmacy, Hubei University of Medicine, Shiyan, 442000, Hubei, China
| | - Chunyan Li
- College of Pharmacy, Sanquan College of Xinxiang Medical University, Xinxiang, 453000, China
| | - Like Fang
- College of Pharmacy, Sanquan College of Xinxiang Medical University, Xinxiang, 453000, China
| | - Lijie Tang
- College of Pharmacy, Sanquan College of Xinxiang Medical University, Xinxiang, 453000, China
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12
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Novoa Díaz MB, Martín MJ, Gentili C. Tumor microenvironment involvement in colorectal cancer progression via Wnt/β-catenin pathway: Providing understanding of the complex mechanisms of chemoresistance. World J Gastroenterol 2022; 28:3027-3046. [PMID: 36051330 PMCID: PMC9331520 DOI: 10.3748/wjg.v28.i26.3027] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 04/29/2022] [Accepted: 06/20/2022] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) continues to be one of the main causes of death from cancer because patients progress unfavorably due to resistance to current therapies. Dysregulation of the Wnt/β-catenin pathway plays a fundamental role in the genesis and progression of several types of cancer, including CRC. In many subtypes of CRC, hyperactivation of the β-catenin pathway is associated with mutations of the adenomatous polyposis coli gene. However, it can also be associated with other causes. In recent years, studies of the tumor microenvironment (TME) have demonstrated its importance in the development and progression of CRC. In this tumor nest, several cell types, structures, and biomolecules interact with neoplastic cells to pave the way for the spread of the disease. Cross-communications between tumor cells and the TME are then established primarily through paracrine factors, which trigger the activation of numerous signaling pathways. Crucial advances in the field of oncology have been made in the last decade. This Minireview aims to actualize what is known about the central role of the Wnt/β-catenin pathway in CRC chemoresistance and aggressiveness, focusing on cross-communication between CRC cells and the TME. Through this analysis, our main objective was to increase the understanding of this complex disease considering a more global context. Since many treatments for advanced CRC fail due to mechanisms involving chemoresistance, the data here exposed and analyzed are of great interest for the development of novel and effective therapies.
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Affiliation(s)
- María Belén Novoa Díaz
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Argentina
| | - María Julia Martín
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Argentina
- Departamento de Química, Universidad Nacional del Sur (UNS)-INQUISUR (CONICET-UNS), Bahía Blanca 8000, Argentina
| | - Claudia Gentili
- Departamento de Biología, Bioquímica y Farmacia, Universidad Nacional del Sur (UNS)-INBIOSUR (CONICET-UNS), Bahía Blanca 8000, Argentina
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13
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Kim NY, Jung YY, Yang MH, Chinnathambi A, Govindasamy C, Narula AS, Namjoshi OA, Blough BE, Ahn KS. Tanshinone IIA exerts autophagic cell death through down-regulation of β-catenin in renal cell carcinoma cells. Biochimie 2022; 200:119-130. [PMID: 35654241 DOI: 10.1016/j.biochi.2022.05.018] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2022] [Revised: 05/21/2022] [Accepted: 05/26/2022] [Indexed: 12/13/2022]
Abstract
Renal cell carcinoma (RCC), also called kidney cancer, is one of the most common malignancies worldwide, including the United States and China. Because of the characteristics of RCC that are both insidious and largely insensitive to chemo-radiation, the incidence and mortality of RCC are increasing every year. However, there are few studies describing anti-cancer effects of the natural compounds on RCC as compared to other cancers. Here, we analyzed the anti-neoplastic impact of Tanshinone IIA (TSN) on RCC cells. We noted that TSN increased the expression of LC3 proteins while having little effect on PARP and Alix protein expression. We found that TSN up-regulated the expression of autophagy-related proteins such as Atg7 and Beclin-1. Moreover, TSN promoted the formation of autophagic vacuoles such as autophagosomes and autolysosomes. However, treatment with 3-Methyladenine (3-MA) or Chloroquine (CQ), slightly decreased the ability of TSN to induce autophagy, but still autophagy occurred. In addition, TSN inhibited translocation of β-catenin into the nucleus, and β-catenin deletion and TSN treatment in RCC increased the expression of LC3 protein. Overall our findings indicate that TSN can exert significant anti-tumor effects through down-regulation of β-catenin to induce autophagic cell death.
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Affiliation(s)
- Na Young Kim
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, South Korea
| | - Young Yun Jung
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, South Korea
| | - Min Hee Yang
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, South Korea
| | - Arunachalam Chinnathambi
- Department of Botany and Microbiology, College of Science, King Saud University, PO Box -2455, Riyadh, 11451, Saudi Arabia
| | - Chandramohan Govindasamy
- Department of Community Health Sciences, College of Applied Medical Sciences, King Saud University, P.O. Box 10219, Riyadh, 11433, Saudi Arabia
| | | | - Ojas A Namjoshi
- Engine Biosciences, 733 Industrial Rd, San Carlos, CA, 94070, USA
| | - Bruce E Blough
- Center for Drug Discovery, RTI International, Research Triangle Park, Durham, NC, 27616, USA
| | - Kwang Seok Ahn
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, South Korea.
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14
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Yang S, Yao L, Wang X, Sun H, Du C, Song C, Fu J, Wu Y, Huang H, Wang C, Wang Y, Xie Y. Exosomes Derived from SW480-Resistant Colon Cancer Cells Are Promote Angiogenesis via BMP-2/Smad5 Signaling Pathway. Appl Bionics Biomech 2022; 2022:6124374. [PMID: 35634178 PMCID: PMC9135529 DOI: 10.1155/2022/6124374] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 04/07/2022] [Accepted: 04/20/2022] [Indexed: 11/17/2022] Open
Abstract
Background Multidrug resistance is the main cause of tumor recurrence and metastasis. Therefore, it is urgent to explore the mechanism and treatment of drug resistance of tumor cells. We aim to investigate the relationship between drug resistance and angiogenesis in SW480 colon cancer cells and the possible underlying mechanism. Methods Exosomes were extracted from SW480-sensitive or SW480-resistant colon cancer cells (SW480/oxaliplatin). The CCK-8 assay, migration assay, tube formation assay, qPCR, and Western blotting were performed in human umbilical vein endothelial cells (HUVECs). The underlying mechanisms were detected by Western blotting assays and BMP-2 si-RNA silencing assay in vitro and in vivo. Results The conditioned medium and exosomes of SW480/oxaliplatin cells promoted proliferation, migration, and tube formation of HUVECs. The expression of BMP-2 released by SW480/oxaliplatin exosomes was 2.3-folds higher than that by SW480 exosomes. Additionally, exosomal BMP-2 inhibiting the Smad signaling pathway induced the expression of vascular endothelial growth factor and CD31. Silencing of BMP-2 partly blocks the promoting effect of SW480/oxaliplatin exosomes on angiogenesis. Moreover, SW480/oxaliplatin cells increased the BMP-2 expression, consequently promoting angiogenesis in vivo. Conclusions SW480-resistant colon cancer exosomes promoted angiogenesis via the BMP-2/Smad signaling pathway, which is potential for the novel treatment for antiangiogenic therapies in colon cancer.
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Affiliation(s)
- Song Yang
- Department of General Surgery, Lu'an Hospital of Anhui Medical University, Lu'an Hospital of Anhui Province, Anhui 237005, China
| | - Lei Yao
- Department of General Surgery, Lu'an Hospital of Anhui Medical University, Lu'an Hospital of Anhui Province, Anhui 237005, China
| | - Xiaolong Wang
- Department of General Surgery, Lu'an Hospital of Anhui Medical University, Lu'an Hospital of Anhui Province, Anhui 237005, China
| | - Hao Sun
- Department of General Surgery, Lu'an Hospital of Anhui Medical University, Lu'an Hospital of Anhui Province, Anhui 237005, China
| | - Chaogang Du
- Department of General Surgery, Lu'an Hospital of Anhui Medical University, Lu'an Hospital of Anhui Province, Anhui 237005, China
| | - Chengpeng Song
- Department of General Surgery, Lu'an Hospital of Anhui Medical University, Lu'an Hospital of Anhui Province, Anhui 237005, China
| | - Jingyu Fu
- Department of General Surgery, Lu'an Hospital of Anhui Medical University, Lu'an Hospital of Anhui Province, Anhui 237005, China
| | - Yongjun Wu
- Department of General Surgery, Lu'an Hospital of Anhui Medical University, Lu'an Hospital of Anhui Province, Anhui 237005, China
| | - Hongwu Huang
- Department of General Surgery, Lu'an Hospital of Anhui Medical University, Lu'an Hospital of Anhui Province, Anhui 237005, China
| | - Chuansi Wang
- Department of General Surgery, Lu'an Hospital of Anhui Medical University, Lu'an Hospital of Anhui Province, Anhui 237005, China
| | - Yongsen Wang
- Department of General Surgery, Lu'an Hospital of Anhui Medical University, Lu'an Hospital of Anhui Province, Anhui 237005, China
| | - Yixiang Xie
- Department of General Surgery, Lu'an Hospital of Anhui Medical University, Lu'an Hospital of Anhui Province, Anhui 237005, China
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15
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Ma J, Zhao X, Shi L. Circ 003390/Eukaryotic translation initiation factor 4A3 promoted cell migration and proliferation in endometrial cancer via vascular endothelial growth factor signaling by miR-195-5p. Bioengineered 2022; 13:11958-11972. [PMID: 35546509 PMCID: PMC9276038 DOI: 10.1080/21655979.2022.2069358] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/02/2022] Open
Abstract
The differential expression of circRNA in different biological samples renders it as an ideal biomarker for disease diagnosis and identification of tissue development. In addition, the gradual clarification of the mode of action of circRNA in disease makes it as a potential therapeutic target. The purpose of this study is to investigate the role and regulating mechanism of circular RNA has circ 003390 (circWEE1) on Endometrial cancer (EC) genesis. To estimate clinical values of circWEE1 on cell migration and proliferation in EC, and its possible mechanisms. The expression of circWEE1 and EIF4A3in EC cells have been evaluated using qPCR and Western blot. The expression of circWEE1 and EIF4A3 levels were increased in patients with EC. Over-expression of circWEE1 or down-regulation of miR-195-5p promoted cell migration and proliferation in EC. Next, we verified that eIF4A3 binds to the circWEE1 mRNA transcript, circWEE1 served as a sponge that directly targeted miR-195-5p. Bioinformatics prediction forecast that miR-195-5p directly targeted VEGF at 3'-UTR, which was confirmed by luciferase reporter assay. Our findings indicate that Circular RNA hsa circWEE1/EIF4A3 promoted cell migration and proliferation in EC via VEGF signaling by miR-195-5p, which could provide pivotal potential therapeutic targets for the treatment of EC.
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Affiliation(s)
- Jing Ma
- Department of Gynecology and Obstetrics, The Forth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Xiwa Zhao
- Department of Gynecology and Obstetrics, The Forth Hospital of Hebei Medical University, Shijiazhuang, China
| | - Li Shi
- Department of Gynecology and Obstetrics, The Forth Hospital of Hebei Medical University, Shijiazhuang, China
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16
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Bhol CS, Mishra SR, Patil S, Sahu SK, Kirtana R, Manna S, Shanmugam MK, Sethi G, Patra SK, Bhutia SK. PAX9 reactivation by inhibiting DNA methyltransferase triggers antitumor effect in oral squamous cell carcinoma. Biochim Biophys Acta Mol Basis Dis 2022; 1868:166428. [PMID: 35533906 DOI: 10.1016/j.bbadis.2022.166428] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2022] [Revised: 04/11/2022] [Accepted: 04/29/2022] [Indexed: 01/07/2023]
Abstract
Aberrant DNA hypermethylation is associated with oral carcinogenesis. Procaine, a local anesthetic, is a DNA methyltransferase (DNMT) inhibitor that activates anticancer mechanisms. However, its effect on silenced tumor suppressor gene (TSG) activation and its biological role in oral squamous cell carcinoma (OSCC) remain unknown. Here, we report procaine inhibited DNA methylation by suppressing DNMT activity and increased the expression of PAX9, a differentiation gene in OSCC cells. Interestingly, the reactivation of PAX9 by procaine found to inhibit cell growth and trigger apoptosis in OSCC in vitro and in vivo. Likely, the enhanced PAX9 expression after exposure to procaine controls stemness and differentiation through the autophagy-dependent pathway in OSCC cells. PAX9 inhibition abrogated procaine-induced apoptosis, autophagy, and inhibition of stemness. In OSCC cells, procaine improved anticancer drug sensitivity through PAX9, and its deficiency significantly blunted the anticancer drug sensitivity mediated by procaine. Additionally, NRF2 activation by procaine facilitated the antitumor response of PAX9, and pharmacological inhibition of NRF2 by ML385 reduced death and prevented the decrease in the orosphere-forming potential of OSCC cells. Furthermore, procaine promoted antitumor activity in FaDu xenografts in athymic nude mice, and immunohistochemistry data showed that PAX9 expression was significantly enhanced in the procaine group compared to the vehicle control. In conclusion, PAX9 reactivation in response to DNMT inhibition could trigger a potent antitumor mechanism to provide a new therapeutic strategy for OSCC.
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Affiliation(s)
- Chandra Sekhar Bhol
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Sundergarh 769008, Odisha, India
| | - Soumya Ranjan Mishra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Sundergarh 769008, Odisha, India
| | - Shankargouda Patil
- Department of Maxillofacial Surgery and Diagnostic Sciences, Division of Oral Pathology, College of Dentistry, Jazan University, Jazan, Saudi Arabia
| | - Sunil Kumar Sahu
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Sundergarh 769008, Odisha, India
| | - R Kirtana
- Epigenetics and Cancer Research Laboratory, Department of Life Science, National Institute of Technology Rourkela, Sundergarh 769008, Odisha, India
| | - Soumen Manna
- Epigenetics and Cancer Research Laboratory, Department of Life Science, National Institute of Technology Rourkela, Sundergarh 769008, Odisha, India
| | - Muthu Kumaraswamy Shanmugam
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
| | - Samir Kumar Patra
- Epigenetics and Cancer Research Laboratory, Department of Life Science, National Institute of Technology Rourkela, Sundergarh 769008, Odisha, India
| | - Sujit Kumar Bhutia
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Sundergarh 769008, Odisha, India.
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17
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Pashirzad M, Sathyapalan T, Sheikh A, Kesharwani P, Sahebkar A. Cancer stem cells: An overview of the pathophysiological and prognostic roles in colorectal cancer. Process Biochem 2022. [DOI: 10.1016/j.procbio.2022.02.006] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
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18
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19
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Li Y, Li Y, Xia J, Yang Q, Chen Y, Sun H. 3'-Sulfo-TF Antigen Determined by GAL3ST2/ST3GAL1 Is Essential for Antitumor Activity of Fungal Galectin AAL/AAGL. ACS OMEGA 2021; 6:17379-17390. [PMID: 34278124 PMCID: PMC8280635 DOI: 10.1021/acsomega.1c01544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2021] [Accepted: 06/04/2021] [Indexed: 06/13/2023]
Abstract
Many lectins have been reported to have antitumor activities; identifying the glycan ligands in tumor cells of lectins is crucial for lectin clinical application. An edible mushroom galectin, Agrocybe aegerita lectin (AAL/AAGL), that has a high antitumor activity has been reported. In this paper, based on the glycan array data, it is showed that the Thomsen-Friedenreich antigen (TF antigen)-related O-glycans were found to be highly correlated with the antitumor activity of AAL/AAGL. Further glycosyltransferase quantification suggested that the ratio between GAL3ST2 and ST3GAL1 (GAL3ST2/ST3GAL1), which determined the 3'-sulfo-TF expression level, was highly correlated with the antitumor activity of AAL/AAGL. Overexpressing the enzyme of GAL3ST2 in HL60 and HeLa cell lines could increase the growth inhibition ratio of AAL/AAGL from 22.7 to 43.9% and 27.8 to 39.1%, respectively. However, ST3GAL1 in Jurkat cells could decrease the growth inhibition ratio from 44.7 to 35.6%. All the data suggested that the 3'-sulfo-TF antigen is one of the main glycan ligands that AAL/AAGL recognizes in tumor cells. AAL/AAGL may potentially serve as a reagent for cancer diagnosis and a targeted therapy for the 3'-sulfo-TF antigen.
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Affiliation(s)
- Yang Li
- College of Life Sciences, Wuhan
University, Wuhan, Hubei Province 430072, P. R. China
| | - Yan Li
- College of Life Sciences, Wuhan
University, Wuhan, Hubei Province 430072, P. R. China
| | - Jing Xia
- College of Life Sciences, Wuhan
University, Wuhan, Hubei Province 430072, P. R. China
| | - Qing Yang
- College
of Food Science and Engineering, Wuhan Polytechnic
University, Wuhan, Hubei Province 430023, P. R. China
| | - Yijie Chen
- College
of Food Science and Technology, Huazhong
Agricultural University, Wuhan, Hubei Province 430070, P. R. China
| | - Hui Sun
- College of Life Sciences, Wuhan
University, Wuhan, Hubei Province 430072, P. R. China
- Hubei
Province key Laboratory of Allergy and Immunology, Wuhan University, Wuhan, Hubei Province 430072, P. R. China
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20
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Xiao Y, Li P, Lu X. Experimental Study on the Effect of miR-200b Regulation of Bone Morphogenetic Protein (BMP)-2 Expression on the Proliferation and Invasion of Nasopharyngeal Carcinoma Cells. J BIOMATER TISS ENG 2021. [DOI: 10.1166/jbt.2021.2707] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
BMP is an important member of the skeletal junction proteins associated with cell invasion, metastasis, and migration. MiR-200b is associated with the progression of several tumors. This study investigated whether miR-200b plays a role in regulating BMP-2 expression and affecting the
proliferation and invasion of nasopharyngeal carcinoma cells. The nasopharyngeal carcinoma tissues with different TNM stages were collected and the proliferative nasal tissues alone were used as controls to detect the expression of miR-200b and BMP by RT-PCR. The nasopharyngeal carcinoma cell
line CNE1 cells were divided into miR-NC group, miR-200b mimic group, siRNA-NC group, and siRNA-BMP-2 group, to detect BMP-2 level, cell invasion and proliferation ability by transwell. The BMP-2 mRNA expressed in nasopharyngeal carcinoma tissues was significantly elevated compared to controls
and correlated with TNM stage. BMP-2 was higher in tumor tissues than in controls, however, the expression profile of miR-200b was opposite to BMP-2. Transfection with miR-200b mimic or siRNA-BMP-2 significantly down-regulated BMP-2 in CNE1 cells and attenuated cell invasive and proliferative
capacity. Reduced expression of miR-200b is associated with elevated BMP-2 expression and increased invasive capacity of nasopharyngeal cancer cells. Overexpression of miR-200b reduces the invasive and proliferative capacity of nasopharyngeal cancer cells by targeting and inhibiting BMP-2
expression.
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Affiliation(s)
- Yi Xiao
- Department of Otorhinolaryngology Head and Neck Surgery, Wuhan Fifth Hospital, Wuhan, Hubei, 430050, China
| | - Peiei Li
- Department of Otorhinolaryngology Head and Neck Surgery, Wuhan Fifth Hospital, Wuhan, Hubei, 430050, China
| | - Xiaoming Lu
- Department of Otorhinolaryngology Head and Neck Surgery, Wuhan Fifth Hospital, Wuhan, Hubei, 430050, China
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21
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Precilla DS, Kuduvalli SS, Purushothaman M, Marimuthu P, Ramachandran MA, Anitha TS. Wnt/β-catenin Antagonists: Exploring New Avenues to Trigger Old Drugs in Alleviating Glioblastoma Multiforme. Curr Mol Pharmacol 2021; 15:338-360. [PMID: 33881978 DOI: 10.2174/1874467214666210420115431] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2020] [Revised: 12/24/2020] [Accepted: 01/30/2021] [Indexed: 11/22/2022]
Abstract
BACKGROUND Glioblastoma multiforme is one of the most heterogenous primary brain tumor with high mortality. Nevertheless, of the current therapeutic approaches, survival rate remains poor with 12 to 15 months following preliminary diagnosis, this warrants the need for effective treatment modality. Wnt/β-catenin pathway is presumably the most noteworthy pathway up-regulated in almost 80% GBM cases contributing to tumor-initiation, progression and survival. Therefore, therapeutic strategies targeting key components of Wnt/β-catenin cascade using established genotoxic agents like temozolomide and pharmacological inhibitors would be an effective approach to modulate Wnt/β-catenin pathway. Recently, drug repurposing by means of effective combination therapy has gained importance in various solid tumors including GBM, by targeting two or more proteins in a single pathway, thereby possessing the ability to overcome the hurdle implicated by chemo-resistance in GBM. OBJECTIVE In this context, by employing computational tools, an attempt has been carried out to speculate the novel combinations against Wnt/β-catenin signaling pathway. METHODS We have explored the binding interactions of three conventional drugs namely temozolomide, metformin, chloroquine along with three natural compounds viz., epigallocatechin gallate, naringenin and phloroglucinol on the major receptors of Wnt/β-catenin signaling. RESULTS It was noted that all the experimental compounds possessed profound interaction with the two major receptors of Wnt/β-catenin pathway. CONCLUSION To the best of our knowledge, this study is the first of its kind to characterize the combined interactions of the afore-mentioned drugs on Wnt/β-catenin signaling in silico and this will putatively open up new avenues for combination therapies in GBM treatment.
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Affiliation(s)
- Daisy S Precilla
- Central Inter-Disciplinary Research Facility, School of Biological Sciences, Sri Balaji Vidyapeeth (Deemed to-be University), Puducherry, India
| | - Shreyas S Kuduvalli
- Central Inter-Disciplinary Research Facility, School of Biological Sciences, Sri Balaji Vidyapeeth (Deemed to-be University), Puducherry, India
| | | | - Parthiban Marimuthu
- Structural Bioinformatics Laboratory - Pharmacy, Faculty of Science and Engineering, Åbo Akademi University, Turku. Finland
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22
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Zhang X, Zhang D, Sun X, Li S, Sun Y, Zhai H. Tumor Suppressor Gene XEDAR Promotes Differentiation and Suppresses Proliferation and Migration of Gastric Cancer Cells Through Upregulating the RELA/LXRα Axis and Deactivating the Wnt/β-Catenin Pathway. Cell Transplant 2021; 30:963689721996346. [PMID: 33637015 PMCID: PMC7923976 DOI: 10.1177/0963689721996346] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2020] [Revised: 01/19/2021] [Accepted: 02/01/2021] [Indexed: 01/06/2023] Open
Abstract
X-linked ectodermal dysplasia receptor (XEDAR) is a new member of the tumor necrosis factor receptor (TNFR) family that induces cell death. The purpose of this study is to determine the tumor-suppressive potential of XEDAR in the development and differentiation of gastric cancer (GC). XEDAR levels were analyzed in human GC tissues and adjacent normal tissues by immunohistochemistry (IHC), quantitative real-time reverse transcription PCR (RT-qPCR), and Western blot analysis. We found that XEDAR expression was significantly downregulated in GC tissues and further decreased in low differentiated GC tissues. Overexpression of XEDAR in MKN45 and MGC803 cells suppressed the ability of cell proliferation and migration, whereas silencing XEDAR showed the opposite effect. Additionally, XEDAR silencing resulted in the upregulation of the differentiation molecular markers β-catenin, CD44 and Cyclin D1 at the protein levels, whereas XEDAR overexpression showed the opposite effect. Notably, XEDAR positively regulated the expression of liver X receptor alpha (LXRα) through upregulating the RELA gene that was characterized as a transcription factor of LXRα in this study. Inhibition of LXRα by GSK2033 or activation of the Wnt/β-catenin pathway by Wnt agonist 1 impaired the effect of XEDAR overexpression on differentiation of MKN45 cells. Moreover, inhibition of RELA mediated by siRNA could promote cell proliferation/migration and rescue the effect of XEDAR overexpression on cell behaviors and expression of genes. Subsequently, overexpression of XEDAR suppressed the growth of GC cells in vivo. Taken together, our findings showed that XEDAR could promote differentiation and suppress proliferation and invasion of GC cells.
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Affiliation(s)
- Xinwu Zhang
- Department of General Surgery, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Di Zhang
- Department of General Surgery, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Xiaoli Sun
- Department of General Surgery, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Shunle Li
- Department of General Surgery, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Yun Sun
- Department of General Surgery, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Hongjun Zhai
- Department of General Surgery, the Second Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
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Liu C, Wang L, Liu X, Tan Y, Tao L, Xiao Y, Deng P, Wang H, Deng Q, Lin Y, Jie H, Zhang H, Zhang J, Peng Y, Zhang H, Zhou Z, Sun Q, Cen X, Zhao Y. Cytoplasmic SHMT2 drives the progression and metastasis of colorectal cancer by inhibiting β-catenin degradation. Am J Cancer Res 2021; 11:2966-2986. [PMID: 33456583 PMCID: PMC7806468 DOI: 10.7150/thno.48699] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Accepted: 12/12/2020] [Indexed: 02/05/2023] Open
Abstract
Introduction: Serine hydroxymethyltransferase 2 (SHMT2) plays a critical role in serine-glycine metabolism to drive cancer cell proliferation. However, the nonmetabolic function of SHMT2 in tumorigenesis, especially in human colorectal cancer (CRC) progression, remains largely unclear. Methods: SHMT2 expression in human CRC cells was identified by western blot and immunofluorescence assay. The CRC cell proliferation, migration, and invasion after SHMT2 knockdown or overexpression were explored through in vitro and in vivo assays. Immunofluorescence, mRNA-seq, co-immunoprecipitation, chromatin immunoprecipitation-qPCR and immunohistochemistry assays were used to investigate the underlying mechanisms behind the SHMT2 nonmetabolic function. Results: We demonstrated that SHMT2 was distributed in the cytoplasm and nucleus of human CRC cells. SHMT2 knockdown resulted in the significant inhibition of CRC cell proliferation, which was not restored by serine, glycine, or formate supplementation. The invasion and migration of CRC cells were suppressed after SHMT2 knockdown. Mechanistically, SHMT2 interacted with β-catenin in the cytoplasm. This interaction inhibited the ubiquitylation-mediated degradation of β-catenin and subsequently modulated the expression of its target genes, leading to the promotion of CRC cell proliferation and metastasis. Notably, the lysine 64 residue on SHMT2 (SHMT2K64) mediated its interaction with β-catenin. Moreover, transcription factor TCF4 interacted with β-catenin, which in turn increased SHMT2 expression, forming an SHMT2/β-catenin positive feedback loop. In vivo xenograft experiments confirmed that SHMT2 promoted the growth and metastasis of CRC cells. Finally, the level of SHMT2 was found to be significantly increased in human CRC tissues. The SHMT2 level was correlated with an increased level of β-catenin, associated with CRC progression and predicted poor patient survival. Conclusion: Taken together, our findings reveal a novel nonmetabolic function of SHMT2 in which it stabilizes β-catenin to prevent its ubiquitylation-mediated degradation and provide a potential therapeutic strategy for CRC therapy.
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Yang J, Ueharu H, Mishina Y. Energy metabolism: A newly emerging target of BMP signaling in bone homeostasis. Bone 2020; 138:115467. [PMID: 32512164 PMCID: PMC7423769 DOI: 10.1016/j.bone.2020.115467] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Revised: 05/29/2020] [Accepted: 06/01/2020] [Indexed: 12/11/2022]
Abstract
Energy metabolism is the process of generating energy (i.e. ATP) from nutrients. This process is indispensable for cell homeostasis maintenance and responses to varying conditions. Cells require energy for growth and maintenance and have evolved to have multiple pathways to produce energy. Both genetic and functional studies have demonstrated that energy metabolism, such as glucose, fatty acid, and amino acid metabolism, plays important roles in the formation and function of bone cells including osteoblasts, osteocytes, and osteoclasts. Dysregulation of energy metabolism in bone cells consequently disturbs the balance between bone formation and bone resorption. Metabolic diseases have also been reported to affect bone homeostasis. Bone morphogenic protein (BMP) signaling plays critical roles in regulating the formation and function of bone cells, thus affecting bone development and homeostasis. Mutations of BMP signaling-related genes in mice have been reported to show abnormalities in energy metabolism in many tissues, including bone. In addition, BMP signaling correlates with critical signaling pathways such as mTOR, HIF, Wnt, and self-degradative process autophagy to coordinate energy metabolism and bone homeostasis. These findings will provide a newly emerging target of BMP signaling and potential therapeutic strategies and the improved management of bone diseases. This review summarizes the recent advances in our understanding of (1) energy metabolism in regulating the formation and function of bone cells, (2) function of BMP signaling in whole body energy metabolism, and (3) mechanistic interaction of BMP signaling with other signaling pathways and biological processes critical for energy metabolism and bone homeostasis.
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Affiliation(s)
- Jingwen Yang
- Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA; The State Key Laboratory Breeding Base of Basic Science of Stomatology & Key Laboratory for Oral Biomedicine of Ministry of Education, School and Hospital of Stomatology, Wuhan University, Wuhan, Hubei 430079, China.
| | - Hiroki Ueharu
- Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA
| | - Yuji Mishina
- Department of Biologic and Materials Sciences, School of Dentistry, University of Michigan, Ann Arbor, MI 48109, USA.
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25
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Pérez-Plasencia C, López-Urrutia E, García-Castillo V, Trujano-Camacho S, López-Camarillo C, Campos-Parra AD. Interplay Between Autophagy and Wnt/β-Catenin Signaling in Cancer: Therapeutic Potential Through Drug Repositioning. Front Oncol 2020; 10:1037. [PMID: 33014767 PMCID: PMC7461967 DOI: 10.3389/fonc.2020.01037] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2020] [Accepted: 05/26/2020] [Indexed: 12/20/2022] Open
Abstract
The widespread dysregulation that characterizes cancer cells has been dissected and many regulation pathways common to multiple cancer types have been described in depth. Wnt/β-catenin signaling and autophagy are among these principal pathways, which contribute to tumor growth and resistance to anticancer therapies. Currently, several therapeutic strategies that target either Wnt/β-catenin signaling or autophagy are in various stages of development. Targeted therapies that block specific elements that participate in both pathways; are subject to in vitro studies as well as pre-clinical and early clinical trials. Strikingly, drugs designed for other diseases also impact these pathways, which is relevant since they are already FDA-approved and sometimes even routinely used in the clinic. The main focus of this mini-review is to highlight the importance of drug repositioning to inhibit the Wnt/β-catenin and autophagy pathways, with an emphasis on the interplay between them. The data we found strongly suggested that this field is worth further examination.
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Affiliation(s)
- Carlos Pérez-Plasencia
- Laboratorio de Genómica Funcional, Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla, Mexico
- Laboratorio de Genómica, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico
| | - Eduardo López-Urrutia
- Laboratorio de Genómica Funcional, Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla, Mexico
| | - Verónica García-Castillo
- Laboratorio de Genómica Funcional, Unidad de Biomedicina, Facultad de Estudios Superiores Iztacala, UNAM, Tlalnepantla, Mexico
| | - Samuel Trujano-Camacho
- Laboratorio de Genómica, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico
| | - César López-Camarillo
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de México, Mexico City, Mexico
| | - Alma D. Campos-Parra
- Laboratorio de Genómica, Instituto Nacional de Cancerología (INCan), Mexico City, Mexico
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Patra S, Mishra SR, Behera BP, Mahapatra KK, Panigrahi DP, Bhol CS, Praharaj PP, Sethi G, Patra SK, Bhutia SK. Autophagy-modulating phytochemicals in cancer therapeutics: Current evidences and future perspectives. Semin Cancer Biol 2020; 80:205-217. [PMID: 32450139 DOI: 10.1016/j.semcancer.2020.05.008] [Citation(s) in RCA: 76] [Impact Index Per Article: 15.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Revised: 05/11/2020] [Accepted: 05/13/2020] [Indexed: 02/08/2023]
Abstract
Autophagy is an intracellular catabolic self-cannibalism that eliminates dysfunctional cytoplasmic cargos by the fusion of cargo-containing autophagosomes with lysosomes to maintain cyto-homeostasis. Autophagy sustains a dynamic interlink between cytoprotective and cytostatic function during malignant transformation in a context-dependent manner. The antioxidant and immunomodulatory phyto-products govern autophagy and autophagy-associated signaling pathways to combat cellular incompetence during malignant transformation. Moreover, in a close cellular signaling circuit, autophagy regulates aberrant epigenetic modulation and inflammation, which limits tumor metastasis. Thus, manipulating autophagy for induction of cell death and associated regulatory phenomena will embark on a new strategy for tumor suppression with wide therapeutic implications. Despite the prodigious availability of lead pharmacophores in nature, the central autophagy regulating entities, their explicit target, as well as pre-clinical and clinical assessment remains a major question to be answered. In addition to this, the stage-specific regulation of autophagy and mode of action with natural products in regulating the key autophagic molecules, control of tumor-specific pathways in relation to modulation of autophagic network specify therapeutic target in caner. Moreover, the molecular pathway specificity and enhanced efficacy of the pre-existing chemotherapeutic agents in co-treatment with these phytochemicals hold high prevalence for target specific cancer therapeutics. Hence, the multi-specific role of phytochemicals in a cellular and tumor context dependent manner raises immense curiosity for investigating of novel therapeutic avenues. In this perspective, this review discusses about diverse implicit mechanisms deployed by the bioactive compounds in diagnosis and therapeutics approach during cancer progression with special insight into autophagic regulation.
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Affiliation(s)
- Srimanta Patra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela 769008, Odisha, India
| | - Soumya R Mishra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela 769008, Odisha, India
| | - Bishnu P Behera
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela 769008, Odisha, India
| | - Kewal K Mahapatra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela 769008, Odisha, India
| | - Debasna P Panigrahi
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela 769008, Odisha, India
| | - Chandra S Bhol
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela 769008, Odisha, India
| | - Prakash P Praharaj
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela 769008, Odisha, India
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
| | - Samir K Patra
- Epigenetics and Cancer Research Laboratory, Biochemistry and Molecular Biology Group, Department of Life Science, National Institute of Technology Rourkela, Rourkela 769008, Odisha, India
| | - Sujit K Bhutia
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Rourkela 769008, Odisha, India.
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Henamayee S, Banik K, Sailo BL, Shabnam B, Harsha C, Srilakshmi S, VGM N, Baek SH, Ahn KS, Kunnumakkara AB. Therapeutic Emergence of Rhein as a Potential Anticancer Drug: A Review of Its Molecular Targets and Anticancer Properties. Molecules 2020; 25:molecules25102278. [PMID: 32408623 PMCID: PMC7288145 DOI: 10.3390/molecules25102278] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 05/02/2020] [Accepted: 05/07/2020] [Indexed: 12/19/2022] Open
Abstract
According to the World Health Organization (WHO), cancer is the second-highest cause of mortality in the world, and it kills nearly 9.6 million people annually. Besides the fatality of the disease, poor prognosis, cost of conventional therapies, and associated side-effects add more burden to patients, post-diagnosis. Therefore, the search for alternatives for the treatment of cancer that are safe, multi-targeted, effective, and cost-effective has compelled us to go back to ancient systems of medicine. Natural herbs and plant formulations are laden with a variety of phytochemicals. One such compound is rhein, which is an anthraquinone derived from the roots of Rheum spp. and Polygonum multiflorum. In ethnomedicine, these plants are used for the treatment of inflammation, osteoarthritis, diabetes, and bacterial and helminthic infections. Increasing evidence suggests that this compound can suppress breast cancer, cervical cancer, colon cancer, lung cancer, ovarian cancer, etc. in both in vitro and in vivo settings. Recent studies have reported that this compound modulates different signaling cascades in cancer cells and can prevent angiogenesis and progression of different types of cancers. The present review highlights the cancer-preventing and therapeutic properties of rhein based on the available literature, which will help to extend further research to establish the chemoprotective and therapeutic roles of rhein compared to other conventional drugs. Future pharmacokinetic and toxicological studies could support this compound as an effective anticancer agent.
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Affiliation(s)
- Sahu Henamayee
- Cancer Biology Laboratory and DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Assam 781039, India; (S.H.); (K.B.); (B.L.S.); (B.S.); (C.H.)
| | - Kishore Banik
- Cancer Biology Laboratory and DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Assam 781039, India; (S.H.); (K.B.); (B.L.S.); (B.S.); (C.H.)
| | - Bethsebie Lalduhsaki Sailo
- Cancer Biology Laboratory and DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Assam 781039, India; (S.H.); (K.B.); (B.L.S.); (B.S.); (C.H.)
| | - Bano Shabnam
- Cancer Biology Laboratory and DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Assam 781039, India; (S.H.); (K.B.); (B.L.S.); (B.S.); (C.H.)
| | - Choudhary Harsha
- Cancer Biology Laboratory and DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Assam 781039, India; (S.H.); (K.B.); (B.L.S.); (B.S.); (C.H.)
| | - Satti Srilakshmi
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER, Guwahati), Assam 781125, India; (S.S.); (N.V.)
| | - Naidu VGM
- Department of Pharmacology & Toxicology, National Institute of Pharmaceutical Education and Research (NIPER, Guwahati), Assam 781125, India; (S.S.); (N.V.)
| | - Seung Ho Baek
- College of Korean Medicine, Dongguk University, 32 Dongguk-ro, Ilsandong-gu, Goyang-si, Gyeonggi-do 10326, Korea;
| | - Kwang Seok Ahn
- Department of Science in Korean Medicine, Kyung Hee University, 24 Kyungheedae-ro, Dongdaemun-gu, Seoul 02447, Korea
- Correspondence: (K.S.A.); or (A.B.K.); Tel.: +82-2-961-2316 (K.S.A.)
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory and DBT-AIST International Laboratory for Advanced Biomedicine (DAILAB), Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Assam 781039, India; (S.H.); (K.B.); (B.L.S.); (B.S.); (C.H.)
- Correspondence: (K.S.A.); or (A.B.K.); Tel.: +82-2-961-2316 (K.S.A.)
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Ashrafizadeh M, Zarrabi A, Saberifar S, Hashemi F, Hushmandi K, Hashemi F, Moghadam ER, Mohammadinejad R, Najafi M, Garg M. Nobiletin in Cancer Therapy: How This Plant Derived-Natural Compound Targets Various Oncogene and Onco-Suppressor Pathways. Biomedicines 2020; 8:biomedicines8050110. [PMID: 32380783 PMCID: PMC7277899 DOI: 10.3390/biomedicines8050110] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Revised: 04/28/2020] [Accepted: 04/28/2020] [Indexed: 02/07/2023] Open
Abstract
Cancer therapy is a growing field, and annually, a high number of research is performed to develop novel antitumor drugs. Attempts to find new antitumor drugs continue, since cancer cells are able to acquire resistance to conventional drugs. Natural chemicals can be considered as promising candidates in the field of cancer therapy due to their multiple-targeting capability. The nobiletin (NOB) is a ubiquitous flavone isolated from Citrus fruits. The NOB has a variety of pharmacological activities, such as antidiabetes, antioxidant, anti-inflammatory, hepatoprotective, and neuroprotective. Among them, the antitumor activity of NOB has been under attention over recent years. In this review, we comprehensively describe the efficacy of NOB in cancer therapy. NOB induces apoptosis and cell cycle arrest in cancer cells. It can suppress migration and invasion of cancer cells via the inhibition of epithelial-to-mesenchymal transition (EMT) and EMT-related factors such as TGF-β, ZEB, Slug, and Snail. Besides, NOB inhibits oncogene factors such as STAT3, NF-κB, Akt, PI3K, Wnt, and so on. Noteworthy, onco-suppressor factors such as microRNA-7 and -200b undergo upregulation by NOB in cancer therapy. These onco-suppressor and oncogene pathways and mechanisms are discussed in this review.
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Affiliation(s)
- Milad Ashrafizadeh
- Department of Basic Science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz 5166616471, Iran;
| | - Ali Zarrabi
- Sabanci University Nanotechnology Research and Application Center (SUNUM), Tuzla, Istanbul 34956, Turkey;
| | - Sedigheh Saberifar
- Department of Basic Sciences, Faculty of Veterinary Medicine, Shahid Chamran University of Ahvaz, Ahvaz 6135783151, Iran;
| | - Farid Hashemi
- DVM. Graduated, Young Researcher and Elite Club, Kazerun Branch, Islamic Azad University, Kazeroon 7319846451, Iran;
| | - Kiavash Hushmandi
- Department of Food Hygiene and Quality Control, Division of Epidemiology, Faculty of Veterinary Medicine, University of Tehran, Tehran 1417414418, Iran;
| | - Fardin Hashemi
- Student Research Committee, Department of Physiotherapy, Faculty of Rehabilitation, Ahvaz Jundishapur University of Medical Sciences, Ahvaz 6135715749, Iran;
| | - Ebrahim Rahmani Moghadam
- Student Research Committee, Department of Anatomical Sciences, School of Medicine, Shiraz University of Medical Sciences, Shiraz 7134814336, Iran;
| | - Reza Mohammadinejad
- Neuroscience Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman 7619813159, Iran
- Correspondence: (R.M.); (M.N.); (M.G.)
| | - Masoud Najafi
- Radiology and Nuclear Medicine Department, School of Paramedical Sciences, Kermanshah University of Medical Sciences, Kermanshah 6715847141, Iran
- Correspondence: (R.M.); (M.N.); (M.G.)
| | - Manoj Garg
- Amity Institute of Molecular Medicine and Stem Cell Research (AIMMSCR), Amity University Uttar Pradesh, Sector-125, Noida-201313, India
- Correspondence: (R.M.); (M.N.); (M.G.)
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29
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Panda PK, Patra S, Naik PP, Praharaj PP, Mukhopadhyay S, Meher BR, Gupta PK, Verma RS, Maiti TK, Bhutia SK. Deacetylation of LAMP1 drives lipophagy-dependent generation of free fatty acids by Abrus agglutinin to promote senescence in prostate cancer. J Cell Physiol 2020; 235:2776-2791. [PMID: 31544977 DOI: 10.1002/jcp.29182] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 08/26/2019] [Indexed: 12/18/2022]
Abstract
Therapy-induced senescence in cancer cells is an irreversible antiproliferative state, which inhibits tumor growth and is therefore a potent anti-neoplastic mechanism. In this study, low doses of Abrus agglutinin (AGG)-induced senescence through autophagy in prostate carcinoma cells (PC3) and inhibited proliferation. The inhibition of autophagy with 3-methyl adenine reversed AGG-induced senescence, thus confirming that AGG-triggered senescence required autophagy. AGG treatment also led to lipophagy-mediated accumulation of free fatty acids (FFAs), with a concomitant decrease in the number of lipid droplets. Lalistat, a lysosomal acid lipase inhibitor, abrogated AGG-induced lipophagy and senescence in PC3 cells, indicating that lipophagy is essential for AGG-induced senescence. The accumulation of FFAs increased reactive oxygen species generation, a known facilitator of senescence, which was also reduced in the presence of lalistat. Furthermore, AGG upregulated silent mating type information regulator 2 homolog 1 (SIRT1), while the presence of sirtinol reduced autophagy flux and the senescent phenotype in the AGG-treated cells. Mechanistically, AGG-induced cytoplasmic SIRT1 deacetylated a Lys residue on the cytoplasmic domain of lysosome-associated membrane protein 1 (LAMP1), an autolysosomal protein, resulting in lipophagy and senescence. Taken together, our findings demonstrate a novel SIRT1/LAMP1/lipophagy axis mediating AGG-induced senescence in prostate cancer cells.
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Affiliation(s)
- Prashanta Kumar Panda
- Department of Life Science, National Institute of Technology Rourkela, Rourkela, India
| | - Srimanta Patra
- Department of Life Science, National Institute of Technology Rourkela, Rourkela, India
| | - Prajna Paramita Naik
- Department of Life Science, National Institute of Technology Rourkela, Rourkela, India
| | | | - Subhadip Mukhopadhyay
- Department of Life Science, National Institute of Technology Rourkela, Rourkela, India
| | | | - Piyush Kumar Gupta
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India
| | - Rama S Verma
- Department of Biotechnology, Bhupat and Jyoti Mehta School of Biosciences, Indian Institute of Technology Madras, Chennai, India
| | - Tapas K Maiti
- Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur, India
| | - Sujit K Bhutia
- Department of Life Science, National Institute of Technology Rourkela, Rourkela, India
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Chen X, Tang FR, Arfuso F, Cai WQ, Ma Z, Yang J, Sethi G. The Emerging Role of Long Non-Coding RNAs in the Metastasis of Hepatocellular Carcinoma. Biomolecules 2019; 10:biom10010066. [PMID: 31906046 PMCID: PMC7023197 DOI: 10.3390/biom10010066] [Citation(s) in RCA: 66] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2019] [Revised: 12/17/2019] [Accepted: 12/17/2019] [Indexed: 12/24/2022] Open
Abstract
Long non-coding RNAs (lncRNAs) play multifaceted roles in modulating gene expression under both physiological and pathological processes. The dysregulation of lncRNAs has been increasingly linked with many human diseases, including a plethora of cancers. Mounting evidence indicates that lncRNAs are aberrantly expressed in hepatocellular carcinoma (HCC) and can regulate HCC progression, as well as metastasis. In this review, we summarize the recent findings on the expanding roles of lncRNAs in modulating various functions of HCC, and elaborate on how can lncRNAs impact HCC metastasis and progression via interacting with chromatin, RNA, and proteins at the epigenetic, transcriptional, and post-transcriptional levels. This mini-review also highlights the current advances regarding the signaling pathways of lncRNAs in HCC metastasis and sheds light on the possible application of lncRNAs for the prevention and treatment of HCC.
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Affiliation(s)
- Xuejiao Chen
- The First School of Clinical Medicine, Health Science Center, Yangtze University, Nanhuan Road, Jingzhou 434023, China;
| | - Feng-Ru Tang
- Radiation Physiology Laboratory, Singapore Nuclear Research and Safety Initiative, National University of Singapore, Singapore 138602, Singapore;
| | - Frank Arfuso
- Stem Cell and Cancer Biology Laboratory, School of Pharmacy and Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, WA 6009, Australia;
| | - Wen-Qi Cai
- School of Basic Medicine, Health Science Center, Yangtze University, 1 Nanhuan Road, Jingzhou 434023, China;
| | - Zhaowu Ma
- The First School of Clinical Medicine, Health Science Center, Yangtze University, Nanhuan Road, Jingzhou 434023, China;
- School of Basic Medicine, Health Science Center, Yangtze University, 1 Nanhuan Road, Jingzhou 434023, China;
- Correspondence: (Z.M.); (J.Y.); (G.S.)
| | - Jiyuan Yang
- The First School of Clinical Medicine, Health Science Center, Yangtze University, Nanhuan Road, Jingzhou 434023, China;
- Correspondence: (Z.M.); (J.Y.); (G.S.)
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- Correspondence: (Z.M.); (J.Y.); (G.S.)
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Yeon M, Lee S, Lee JE, Jung HS, Kim Y, Jeoung D. CAGE-miR-140-5p-Wnt1 Axis Regulates Autophagic Flux, Tumorigenic Potential of Mouse Colon Cancer Cells and Cellular Interactions Mediated by Exosomes. Front Oncol 2019; 9:1240. [PMID: 31799196 PMCID: PMC6868029 DOI: 10.3389/fonc.2019.01240] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2019] [Accepted: 10/28/2019] [Indexed: 12/12/2022] Open
Abstract
Although the cancer/testis antigen CAGE has been implicated in tumorigenesis, the molecular mechanisms of CAGE-promoted tumorigenesis remain largely unknown. CT26Flag−CAGE cells, CT26 (mouse colon cancer cells) cells stably expressing CAGE, were established to investigate CAGE-promoted tumorigenesis. Down-regulation of CAGE led to decreased autophagic flux in CT26Flag−CAGE cells. CAGE interacted with Beclin1, a mediator of autophagy. The CT26Flag−CAGE cells showed enhanced autophagosome formation and displayed greater tumor spheroid-forming potential than CT26 cells. MicroRNA array analysis revealed that CAGE decreased the expression of various microRNAs, including miR-140-5p, in CT26 cells. CAGE was shown to bind to the promoter sequences of miR-140-5p. MiR-140-5p inhibition increased the tumorigenic potential of and autophagic flux in CT26 cells. A miR-140-5p mimic exerted negative effects on the tumorigenic potential of CT26Flag−CAGE cells and autophagic flux in CT26Flag−CAGE cells. MiR-140-5p was predicted to bind to the 3′-UTR of Wnt1. CT26Flag−CAGE cells showed higher expression of Wnt1 than CT26 cells. Down-regulation of Wnt1 decreased autophagic flux. Luciferase activity assays showed the direct regulation of wnt1 by miR-140-5p. Tumor tissue derived from the CT26Flag−CAGE cells revealed higher expressions of factors associated with activated mast cells and tumor-associated macrophages than tumor tissue derived from CT26 cells. Culture medium from the CT26Flag−CAGE cells increased autophagic flux in CT26 cells, mast cells and macrophages. Culture medium from the CT26Flag−CAGE cells increased CD163 and autophagic flux in CT26 cells, mast cells, and macrophages in a Wnt1-dependent manner. Exosomes from CT26Flag−CAGE cells increased autophagc flux in CT26 cells, mast cells, and macrophages. Exosomes from CT26Flag−CAGE cells increased the tumorigenic potential of CT26 cells. Wnt1 was shown to be present within the exosomes. Recombinant Wnt1 protein increased autophagic flux in CT26, mast cells, and macrophages. Recombinant wnt1 protein mediated interactions between the CT26 cells, mast cells, and macrophages. Our results showed novel roles for the CAGE-miR-140-5p-Wnt1 axis in autophagic flux and cellular interactions mediated by exosomes.
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Affiliation(s)
- Minjeong Yeon
- Department of Biochemistry, Kangwon National University, Chuncheon-si, South Korea
| | - Seungheon Lee
- Department of Biochemistry, Kangwon National University, Chuncheon-si, South Korea
| | - Joo-Eun Lee
- Department of Biochemistry, Kangwon National University, Chuncheon-si, South Korea
| | - Hyun Suk Jung
- Department of Biochemistry, Kangwon National University, Chuncheon-si, South Korea
| | - Youngmi Kim
- College of Medicine, Institute of New Frontier Research, Hallym University, Chuncheon-si, South Korea
| | - Dooil Jeoung
- Department of Biochemistry, Kangwon National University, Chuncheon-si, South Korea
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Cai B, Zheng Y, Yan J, Wang J, Liu X, Yin G. BMP2-mediated PTEN enhancement promotes differentiation of hair follicle stem cells by inducing autophagy. Exp Cell Res 2019; 385:111647. [PMID: 31562859 DOI: 10.1016/j.yexcr.2019.111647] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Revised: 09/09/2019] [Accepted: 09/24/2019] [Indexed: 12/13/2022]
Abstract
The proliferation and differentiation of hair follicle stem cells (HFSCs) is regulated by several signaling pathways, including BMP and PTEN. Therefore, this study intended to clarify the potential effects of two such regulators, BMP2 and PTEN, on HFSC differentiation. HFSCs were subjected to BMP2, noggin (BMP2 ligand inhibitor), rapamycin (Rapa, autophagy inducer), 3-methyladenine (3-MA, autophagy inhibitor), or shRNA against PTEN. The differentiation of HFSCs was evaluated using oil red O staining and autophagy was assessed using the transmission electron microscope. Then expression of epidermal differentiation marker (K10 and involucrin), adipogenic markers (PPAR-γ2, aP2, perilipin2, and Adipoq), keratinocyte-specific marker (K15), proliferation-related markers (PCNA and Ki67) and autophagy-related factors (Atg5, Atg7, Atg12, Beclin-1 and LC3-II/LC3-I) was examined by RT-qPCR and Western blot analysis. Next, HFSCs were treated with 3-MA, or shRNA against Atg5 or Atg7 to verify the effect of autophagy on differentiation of BMP2-treated HFSCs. Finally, the effect of BMP2 on HFSC differentiation was verified by a mouse wound model. HFSCs overexpressing BMP2 exhibited elevated expression of epidermal differentiation marker, adipogenic markers and autophagy-related factors but inhibited expression of keratinocyte-specific marker and proliferation-related markers. Furthermore, we found that PTEN promoted the differentiation of BMP2-treated HFSCs by inducing autophagy. In vivo experiments further confirmed the roles of BMP2/PTEN on differentiation of HFSCs. Taken together, BMP2 up-regulated PTEN and consequently induced autophagy to facilitate HFSC differentiation.
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Affiliation(s)
- Bingjie Cai
- Department of Dermatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China
| | - Yunpeng Zheng
- Department of Dermatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China
| | - Jiadi Yan
- Department of Dermatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China
| | - Junmin Wang
- College of Basic Medical Sciences, Zhengzhou University, Zhengzhou, 450001, PR China
| | - Xiaojun Liu
- Henan Province Medical Instrument Testing Institute, Zhengzhou, 450018, PR China
| | - Guangwen Yin
- Department of Dermatology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, PR China.
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Gu Q, Luo Y, Chen C, Jiang D, Huang Q, Wang X. GREM1 overexpression inhibits proliferation, migration and angiogenesis of osteosarcoma. Exp Cell Res 2019; 384:111619. [PMID: 31525341 DOI: 10.1016/j.yexcr.2019.111619] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2019] [Revised: 08/31/2019] [Accepted: 09/06/2019] [Indexed: 12/12/2022]
Abstract
Osteosarcoma is the most common malignancy of bone that occurs in young adults and children, with a five-year survival rate of 60-70%. Metastasis of osteosarcoma maintains an even poorer prognosis. GREM1 plays an important role in regulating organogenesis, body patterning, and tissue differentiation. However, there are limited studies on GREM1 in osteosarcomas. This study was carried out to characterize the expression and function of GREM1 in osteosarcoma cells, thus extending our understanding of osteosarcoma metastasis. GREM1 expression was detected in hBMSC, hFOB1.19, Saos-2, MG63 and U2OS cell lines using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot analysis. Gain- and loss-of-function approaches were used to assess the biological function of GREM1 in U2OS cells. The effects of GREM1 on U2OS cell proliferation were examined using the CCK-8 and colony formation assay. Migration and invasion ability were confirmed by the wound healing and Transwell assay, respectively. Flow cytometry was used to analyse the effect of GREM1 on the cell cycle and apoptosis. The expression of GREM1 targets was evaluated by qRT-PCR and western blotting. The expression of GREM1 was significantly downregulated in osteosarcoma. GREM1 overexpression inhibited the proliferation, migration and invasion of U2OS cells. GREM1 overexpression suppressed tumour cell-induced endothelial cell migration and invasion ability. The effect of GREM1 may be transduced through regulation of the BMP target transcription factor inhibitor of MMP-2 and -9 as well as Id1. GREM1 overexpression and knockdown regulates the tumorigenesis of osteosarcoma in vivo. In conclusion, GREM1 is downregulated in osteosarcoma cells, and overexpression of GREM1 inhibits the proliferation, migration, invasion and angiogenesis abilities of osteosarcoma cells in vitro and in vivo.
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Affiliation(s)
- Qingguo Gu
- Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai, 200003, China
| | - Yibin Luo
- Department of Orthopedics, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai, 200003, China
| | - Cheng Chen
- Department of Orthopedics, Shanghai University of Medicine &health Sciences Affiliated Zhoupu Hospital, China
| | - Dongjie Jiang
- Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai, 200003, China.
| | - Quan Huang
- Department of Orthopedic Oncology, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai, 200003, China.
| | - Xinwei Wang
- Department of Orthopedics, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai, 200003, China.
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Panigrahi DP, Praharaj PP, Bhol CS, Mahapatra KK, Patra S, Behera BP, Mishra SR, Bhutia SK. The emerging, multifaceted role of mitophagy in cancer and cancer therapeutics. Semin Cancer Biol 2019; 66:45-58. [PMID: 31351198 DOI: 10.1016/j.semcancer.2019.07.015] [Citation(s) in RCA: 198] [Impact Index Per Article: 33.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2019] [Revised: 06/26/2019] [Accepted: 07/22/2019] [Indexed: 12/18/2022]
Abstract
Mitophagy is an evolutionarily conserved cellular process which selectively eliminates dysfunctional mitochondria by targeting them to the autophagosome for degradation. Dysregulated mitophagy results in the accumulation of damaged mitochondria, which plays an important role in carcinogenesis and tumor progression. The role of mitophagy receptors and adaptors including PINK1, Parkin, BNIP3, BNIP3L/NIX, and p62/SQSTM1, and the signaling pathways that govern mitophagy are impaired in cancer. Furthermore, the contribution of mitophagy in regulating the metabolic switch may establish a balance between aerobic glycolysis and oxidative phosphorylation for cancer cell survival. Moreover, ROS-driven mitophagy achieves different goals depending on the stage of tumorigenesis. Mitophagy promotes plasticity in the cancer stem cell through the metabolic reconfiguration for better adaption to the tumor microenvironment. In addition, the present review sheds some light on the role of mitophagy in stemness and differentiation during the transition of cell's fate, which could have a crucial role in cancer progression and metastasis. In conclusion, this review deals with the detailed molecular mechanisms underlying mitophagy, along with highlighting the dual role of mitophagy in different aspects of cancer, suggesting it as a possible target in the mitophagy-modulated cancer therapy.
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Affiliation(s)
- Debasna P Panigrahi
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha, India
| | - Prakash P Praharaj
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha, India
| | - Chandra S Bhol
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha, India
| | - Kewal K Mahapatra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha, India
| | - Srimanta Patra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha, India
| | - Bishnu P Behera
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha, India
| | - Soumya R Mishra
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha, India
| | - Sujit K Bhutia
- Cancer and Cell Death Laboratory, Department of Life Science, National Institute of Technology Rourkela, Odisha, India.
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35
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Bhutia SK, Panda PK, Sinha N, Praharaj PP, Bhol CS, Panigrahi DP, Mahapatra KK, Saha S, Patra S, Mishra SR, Behera BP, Patil S, Maiti TK. Plant lectins in cancer therapeutics: Targeting apoptosis and autophagy-dependent cell death. Pharmacol Res 2019; 144:8-18. [PMID: 30951812 DOI: 10.1016/j.phrs.2019.04.001] [Citation(s) in RCA: 76] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 03/20/2019] [Accepted: 04/01/2019] [Indexed: 12/18/2022]
Abstract
Plant lectins are non-immunoglobin in nature and bind to the carbohydrate moiety of the glycoconjugates without altering any of the recognized glycosyl ligands. Plant lectins have found applications as cancer biomarkers for recognizing the malignant tumor cells for the diagnosis and prognosis of cancer. Interestingly, plant lectins contribute to inducing cell death through autophagy and apoptosis, indicating their potential implication in cancer inhibitory mechanism. In the present review, anticancer activities of major plant lectins have been documented, with a detailed focus on the signaling circuit for the possible molecular targeted cancer therapy. In this context, several lectins have exhibited preclinical and clinical significance, driving toward therapeutic potential in cancer treatment. Moreover, several plant lectins induce immunomodulatory activities, and therefore, novel strategies have been established from preclinical and clinical investigations for the development of combinatorial treatment consisting of immunotherapy along with other anticancer therapies. Although the application of plant lectins in cancer is still in very preliminary stage, advanced high-throughput technology could pave the way for the development of lectin-based complimentary medicine for cancer treatment.
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Affiliation(s)
- Sujit K Bhutia
- Department of Life Science, National Institute of Technology Rourkela, India.
| | - Prashanta K Panda
- Department of Life Science, National Institute of Technology Rourkela, India
| | - Niharika Sinha
- Department of Life Science, National Institute of Technology Rourkela, India
| | - Prakash P Praharaj
- Department of Life Science, National Institute of Technology Rourkela, India
| | - Chandra S Bhol
- Department of Life Science, National Institute of Technology Rourkela, India
| | - Debasna P Panigrahi
- Department of Life Science, National Institute of Technology Rourkela, India
| | - Kewal K Mahapatra
- Department of Life Science, National Institute of Technology Rourkela, India
| | - Sarbari Saha
- Department of Life Science, National Institute of Technology Rourkela, India
| | - Srimanta Patra
- Department of Life Science, National Institute of Technology Rourkela, India
| | - Soumya R Mishra
- Department of Life Science, National Institute of Technology Rourkela, India
| | - Bishnu P Behera
- Department of Life Science, National Institute of Technology Rourkela, India
| | - Shankargouda Patil
- Department of Maxillofacial Surgery and Diagnostic Sciences, Division of Oral Pathology, College of Dentistry, Jazan University, Saudi Arabia
| | - Tapas K Maiti
- Department of Biotechnology, Indian Institute of Technology Kharagpur, Kharagpur-721302, India
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