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Liu K, Bie J, Zhang R, Xiong R, Peng L, Luo Y, Yang S, Feng G, Song G. AGTR1 potentiates the chemotherapeutic efficacy of cisplatin in esophageal carcinoma through elevation of intracellular Ca 2+ and induction of apoptosis. Int J Oncol 2025; 66:32. [PMID: 40084687 PMCID: PMC11900935 DOI: 10.3892/ijo.2025.5738] [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: 01/04/2024] [Accepted: 10/25/2024] [Indexed: 03/16/2025] Open
Abstract
Cisplatin is one of the principal chemotherapeutic agents used for esophageal cancer (EC) treatment; however, EC mortality remains high. It is therefore imperative to find new therapeutic targets and approaches to potentiate the chemotherapeutic efficacy of cisplatin. Angiotensin II receptor type 1 (AGTR1) is a potential therapeutic target in multiple cancer types. In the present study, RNA‑sequencing analysis of EC and normal esophageal tissues was performed and AGTR1 was identified as a differentially expressed gene that is markedly downregulated in recurrent and metastasized EC. AGTR1 upregulation in the esophageal squamous cell carcinoma cell lines, KYSE‑150 and EC109, promoted their chemosensitivity to cisplatin both in vitro and in vivo. Additionally, AGTR1 suppressed the metastasis‑relevant traits of EC cells, as evidenced by the reduced migration, invasion and wound healing of EC cells with higher AGTR1 expression levels. Moreover, AGTR1 overexpression in EC cells upregulated intracellular Ca2+ levels, reduced ATP levels and mitochondrial membrane potentials, which was accompanied by enhanced mitochondrial pathway apoptosis. Notably, either AGTR1 overexpression or treatments with the calcium channel blocker, fendiline, caused Ca2+ influx and promoted mitochondria‑dependent apoptosis in KYSE‑150 cells in vitro. These effects were augmented when both AGTR1 overexpression and fendiline stimulation were imposed in the absence or presence of cisplatin treatments. Furthermore, fendiline administration enhanced the chemosensitivity of cisplatin in an EC xenograft mouse model. Collectively, these findings offer an alternative treatment option and provide mechanistic insights into using fendiline to potentiate the chemotherapy efficacy of cisplatin in treating EC.
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Affiliation(s)
- Kang Liu
- Institute of Tissue Engineering and Stem Cells, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Jun Bie
- Department of Oncology, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Ruolan Zhang
- Institute of Tissue Engineering and Stem Cells, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Rong Xiong
- Institute of Tissue Engineering and Stem Cells, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Lihong Peng
- Institute of Tissue Engineering and Stem Cells, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Yi Luo
- Institute of Tissue Engineering and Stem Cells, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Siyun Yang
- Institute of Tissue Engineering and Stem Cells, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Gang Feng
- Institute of Tissue Engineering and Stem Cells, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
| | - Guiqin Song
- Institute of Tissue Engineering and Stem Cells, Nanchong Central Hospital, The Second Clinical Medical College, North Sichuan Medical College, Nanchong, Sichuan 637000, P.R. China
- School of Basic Medicine and Forensic Sciences, North Sichuan Medical College, Nanchong, Sichuan 637100, P.R. China
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Wang P, Zhang X, Shen J. Prognostic impact of renin-angiotensin system inhibitors in patients with ovarian cancer: a meta-analysis of real-world evidence. Expert Rev Anticancer Ther 2025. [PMID: 39907527 DOI: 10.1080/14737140.2025.2463486] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2024] [Revised: 01/29/2025] [Accepted: 02/02/2025] [Indexed: 02/06/2025]
Abstract
BACKGROUND The prognostic impact of renin-angiotensin system inhibitors (RASIs) on ovarian cancer (OC) remains indeterminate. This meta-analysis aims to consolidate real-world data to provide a comprehensive, evidence-based assessment of the association between RASIs use and clinical outcomes in OC patients. METHODS A meticulous search strategy was devised and executed across PubMed, Scopus, and Embase databases to retrieve all relevant studies evaluating the prognostic impact of RASIs in patients with OC. Studies comparing survival outcomes between RASIs users and non-users were included in the meta-analysis. The risk of publication bias was assessed using funnel plot and Egger's test. Sensitivity analysis employing the leave-one-out approach was performed to ensure the robustness and reliability of the pooled estimates. RESULTS A total of six studies, encompassing eleven cohorts and 14,634 patients, were included in the meta-analysis. RASIs use was found to be significantly correlated with enhanced survival (HR: 0.82; 95%CI: 0.72-0.92) in the OC patient population. Subgroup analysis showed that ACEIs use (HR: 0.83, 95% CI: 0.78-0.89) and post-diagnostic RASIs use (HR: 0.77, 95% CI: 0.66-0.90) significantly improved overall survival. Sensitivity analysis confirmed the consistency and stability of the pooled results. CONCLUSION This meta-analysis provides evidence that RASIs are associated with improved prognosis in OC patients. These findings suggest that RASIs may have potential as an adjunctive therapy in the management of OC, warranting further investigation and consideration in clinical management protocols.
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Affiliation(s)
- Pian Wang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, PR China
- Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, Jiangsu, PR China
| | - Xinmiao Zhang
- College of Integrated Traditional Chinese and Western Medicine, Hebei University of Chinese Medicine, Shijiazhuang, Hebei Province, PR China
- The Second Hospital of Hebei Medicine University, Shijiazhuang, Hebei Province, PR China
| | - Jinhai Shen
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, Jiangsu, PR China
- Center for New Drug Safety Evaluation and Research, China Pharmaceutical University, Nanjing, Jiangsu, PR China
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Liu Y, Xiao H, Zeng H, Xiang Y. Beyond tumor‑associated macrophages involved in spheroid formation and dissemination: Novel insights for ovarian cancer therapy (Review). Int J Oncol 2024; 65:117. [PMID: 39513610 PMCID: PMC11575928 DOI: 10.3892/ijo.2024.5705] [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: 05/24/2024] [Accepted: 10/22/2024] [Indexed: 11/15/2024] Open
Abstract
Ovarian cancer (OC) is the most common and deadly malignant tumor of the female reproductive system. When OC cells detach from the primary tumor and enter the ascitic microenvironment, they are present as individual cells or multicellular spheroids in ascites. These spheroids, composed of cancer and non‑malignant cells, are metastatic units and play a crucial role in the progression of OC. However, little is known about the mechanism of spheroid formation and dissemination. Tumor‑associated macrophages (TAMs) in the center of spheroids are key in spheroid formation and metastasis and provide a potential target for OC therapy. The present review summarizes the key biological features of spheroids, focusing on the role of TAMs in spheroid formation, survival and peritoneal metastasis, and the strategies targeting TAMs to provide new insights in treating OC.
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Affiliation(s)
- Yuchen Liu
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, P.R. China
| | - Haoyue Xiao
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, P.R. China
| | - Hai Zeng
- Department of Oncology, First Affiliated Hospital of Yangtze University, Jingzhou, Hubei 434023, P.R. China
| | - Ying Xiang
- Laboratory of Oncology, Center for Molecular Medicine, School of Basic Medicine, Health Science Center, Yangtze University, Jingzhou, Hubei 434023, P.R. China
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Liu S, Dai W, Jin B, Jiang F, Huang H, Hou W, Lan J, Jin Y, Peng W, Pan J. Effects of super-enhancers in cancer metastasis: mechanisms and therapeutic targets. Mol Cancer 2024; 23:122. [PMID: 38844984 PMCID: PMC11157854 DOI: 10.1186/s12943-024-02033-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 05/28/2024] [Indexed: 06/09/2024] Open
Abstract
Metastasis remains the principal cause of cancer-related lethality despite advancements in cancer treatment. Dysfunctional epigenetic alterations are crucial in the metastatic cascade. Among these, super-enhancers (SEs), emerging as new epigenetic regulators, consist of large clusters of regulatory elements that drive the high-level expression of genes essential for the oncogenic process, upon which cancer cells develop a profound dependency. These SE-driven oncogenes play an important role in regulating various facets of metastasis, including the promotion of tumor proliferation in primary and distal metastatic organs, facilitating cellular migration and invasion into the vasculature, triggering epithelial-mesenchymal transition, enhancing cancer stem cell-like properties, circumventing immune detection, and adapting to the heterogeneity of metastatic niches. This heavy reliance on SE-mediated transcription delineates a vulnerable target for therapeutic intervention in cancer cells. In this article, we review current insights into the characteristics, identification methodologies, formation, and activation mechanisms of SEs. We also elaborate the oncogenic roles and regulatory functions of SEs in the context of cancer metastasis. Ultimately, we discuss the potential of SEs as novel therapeutic targets and their implications in clinical oncology, offering insights into future directions for innovative cancer treatment strategies.
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Affiliation(s)
- Shenglan Liu
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Jiangxi Provincal Key Laboratory of Tissue Engineering, School of Pharmacy, Gannan Medical University, Ganzhou, 314000, China
| | - Wei Dai
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Jiangxi Provincal Key Laboratory of Tissue Engineering, School of Pharmacy, Gannan Medical University, Ganzhou, 314000, China
| | - Bei Jin
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, China
| | - Feng Jiang
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Jiangxi Provincal Key Laboratory of Tissue Engineering, School of Pharmacy, Gannan Medical University, Ganzhou, 314000, China
| | - Hao Huang
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Jiangxi Provincal Key Laboratory of Tissue Engineering, School of Pharmacy, Gannan Medical University, Ganzhou, 314000, China
| | - Wen Hou
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Jiangxi Provincal Key Laboratory of Tissue Engineering, School of Pharmacy, Gannan Medical University, Ganzhou, 314000, China
| | - Jinxia Lan
- College of Public Health and Health Management, Gannan Medical University, Ganzhou, 341000, China
| | - Yanli Jin
- College of Pharmacy, Jinan University Institute of Tumor Pharmacology, Jinan University, Guangzhou, 510632, China
| | - Weijie Peng
- Key Laboratory of Prevention and Treatment of Cardiovascular and Cerebrovascular Diseases, Ministry of Education, Jiangxi Provincal Key Laboratory of Tissue Engineering, School of Pharmacy, Gannan Medical University, Ganzhou, 314000, China.
| | - Jingxuan Pan
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, 510060, China.
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Guo Z, Huo X, Li X, Jiang C, Xue L. Advances in regulation and function of stearoyl-CoA desaturase 1 in cancer, from bench to bed. SCIENCE CHINA. LIFE SCIENCES 2023; 66:2773-2785. [PMID: 37450239 DOI: 10.1007/s11427-023-2352-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/15/2023] [Accepted: 04/23/2023] [Indexed: 07/18/2023]
Abstract
Stearoyl-CoA desaturase 1 (SCD1) converts saturated fatty acids to monounsaturated fatty acids. The expression of SCD1 is increased in many cancers, and the altered expression contributes to the proliferation, invasion, sternness and chemoresistance of cancer cells. Recently, more evidence has been reported to further support the important role of SCD1 in cancer, and the regulation mechanism of SCD1 has also been focused. Multiple factors are involved in the regulation of SCD1, including metabolism, diet, tumor microenvironment, transcription factors, non-coding RNAs, and epigenetics modification. Moreover, SCD1 is found to be involved in regulating ferroptosis resistance. Based on these findings, SCD1 has been considered as a potential target for cancer treatment. However, the resistance of SCD1 inhibition may occur in certain tumors due to tumor heterogeneity and metabolic plasticity. This review summarizes recent advances in the regulation and function of SCD1 in tumors and discusses the potential clinical application of targeting SCD1 for cancer treatment.
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Affiliation(s)
- Zhengyang Guo
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, 100191, China
| | - Xiao Huo
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, 100191, China
| | - Xianlong Li
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, 100191, China
| | - Changtao Jiang
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, 100191, China.
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University and the Key Laboratory of Molecular Cardiovascular Science (Peking University), Ministry of Education, Beijing, 100191, China.
| | - Lixiang Xue
- Center of Basic Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing, 100191, China.
- Peking University Third Hospital Cancer Center, Department of Radiation Oncology, Peking University Third Hospital, Beijing, 100191, China.
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Yan T, Ma X, Guo L, Lu R. Targeting endoplasmic reticulum stress signaling in ovarian cancer therapy. Cancer Biol Med 2023; 20:j.issn.2095-3941.2023.0232. [PMID: 37817482 PMCID: PMC10618951 DOI: 10.20892/j.issn.2095-3941.2023.0232] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2023] [Accepted: 09/05/2023] [Indexed: 10/12/2023] Open
Abstract
The endoplasmic reticulum (ER), an organelle present in various eukaryotic cells, is responsible for intracellular protein synthesis, post-translational modification, and folding and transport, as well as the regulation of lipid and steroid metabolism and Ca2+ homeostasis. Hypoxia, nutrient deficiency, and a low pH tumor microenvironment lead to the accumulation of misfolded or unfolded proteins in the ER, thus activating ER stress (ERS) and the unfolded protein response, and resulting in either restoration of cellular homeostasis or cell death. ERS plays a crucial role in cancer oncogenesis, progression, and response to therapies. This article reviews current studies relating ERS to ovarian cancer, the most lethal gynecologic malignancy among women globally, and discusses pharmacological agents and possible targets for therapeutic intervention.
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Affiliation(s)
- Tianqing Yan
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Xiaolu Ma
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Lin Guo
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
| | - Renquan Lu
- Department of Clinical Laboratory, Fudan University Shanghai Cancer Center, Shanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China
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7
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Pal S, Bhowmick S, Sharma A, Sierra-Fonseca JA, Mondal S, Afolabi F, Roy D. Lymphatic vasculature in ovarian cancer. Biochim Biophys Acta Rev Cancer 2023; 1878:188950. [PMID: 37419192 PMCID: PMC10754213 DOI: 10.1016/j.bbcan.2023.188950] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 06/29/2023] [Accepted: 06/29/2023] [Indexed: 07/09/2023]
Abstract
Ovarian cancer (OVCA) is the second most common gynecological cancer and one of the leading causes of cancer related mortality among women. Recent studies suggest that among ovarian cancer patients at least 70% of the cases experience the involvement of lymph nodes and metastases through lymphatic vascular network. However, the impact of lymphatic system in the growth, spread and the evolution of ovarian cancer, its contribution towards the landscape of ovarian tissue resident immune cells and their metabolic responses is still a major knowledge gap. In this review first we present the epidemiological aspect of the OVCA, the lymphatic architecture of the ovary, we discuss the role of lymphatic circulation in regulation of ovarian tumor microenvironment, metabolic basis of the upregulation of lymphangiogenesis which is often observed during progression of ovarian metastasis and ascites development. Further we describe the implication of several mediators which influence both lymphatic vasculature as well as ovarian tumor microenvironment and conclude with several therapeutic strategies for targeting lymphatic vasculature in ovarian cancer progression in present day.
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Affiliation(s)
- Sarit Pal
- Department of Medical Physiology, College of Medicine, Texas A&M University, Bryan, TX 77843, United States
| | - Sramana Bhowmick
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata 700073, West Bengal, India
| | - Anurag Sharma
- Pathology and Laboratory Medicine, Cleveland Clinic, Cleveland, OH, United States
| | | | - Susmita Mondal
- Department of Life Sciences, Presidency University, 86/1 College Street, Kolkata 700073, West Bengal, India
| | - Favour Afolabi
- Department of Biological Sciences, Alcorn State University, Lorman, MS 39096, United States
| | - Debarshi Roy
- Department of Biological Sciences, Alcorn State University, Lorman, MS 39096, United States.
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Agarwal S, Afaq F, Bajpai P, Behring M, Kim HG, Varambally A, Chandrashekar DS, Peter S, Al Diffalha S, Khushman M, Seeber A, Varambally S, Manne U. BZW2 Inhibition Reduces Colorectal Cancer Growth and Metastasis. Mol Cancer Res 2023; 21:698-712. [PMID: 37067340 PMCID: PMC10329991 DOI: 10.1158/1541-7786.mcr-23-0003] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2023] [Revised: 02/06/2023] [Accepted: 03/17/2023] [Indexed: 04/18/2023]
Abstract
Because survival of patients with metastatic colorectal cancer remain poor, there is an urgent need to identify potential novel druggable targets that are associated with colorectal cancer progression. One such target, basic leucine zipper and W2 domains 2 (BZW2), is involved in regulation of protein translation, and its overexpression is associated with human malignancy. Thus, we investigated the expression and regulation of BZW2, assessed its role in activation of WNT/β-catenin signaling, identified its downstream molecules, and demonstrated its involvement in metastasis of colorectal cancer. In human colorectal cancers, high mRNA and protein expression levels of BZW2 were associated with tumor progression. BZW2-knockdown reduced malignant phenotypes, including cell proliferation, invasion, and spheroid and colony formation. BZW2-knockdown also reduced tumor growth and metastasis; conversely, transfection of BZW2 into BZW2 low-expressing colorectal cancer cells promoted malignant features, including tumor growth and metastasis. BZW2 expression was coordinately regulated by microRNA-98, c-Myc, and histone methyltransferase enhancer of zeste homolog 2 (EZH2). RNA sequencing analyses of colorectal cancer cells modulated for BZW2 identified P4HA1 and the long noncoding RNAs, MALAT1 and NEAT1, as its downstream targets. Further, BZW2 activated the Wnt/β-catenin signaling pathway in colorectal cancers expressing wild-type β-catenin. In sum, our study suggests the possibility of targeting BZW2 expression by inhibiting EZH2 and/or c-Myc. IMPLICATIONS FDA-approved small-molecule inhibitors of EZH2 can indirectly target BZW2 and because BZW2 functions as an oncogene, these inhibitors could serve as therapeutic agents for colorectal cancer.
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Affiliation(s)
- Sumit Agarwal
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL
| | - Farrukh Afaq
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL
| | - Prachi Bajpai
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL
| | - Michael Behring
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL
| | - Hyung-Gyoon Kim
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL
| | | | | | - Shajan Peter
- Department of Medicine, Division of Gastroenterology, University of Alabama at Birmingham, Birmingham, AL
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL
| | - Sameer Al Diffalha
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL
| | - Moh’d Khushman
- Department of Medicine, Division of Hematology and Oncology, Washington University, St. Louis, MO
| | - Andreas Seeber
- Department of Hematology and Oncology, Comprehensive Cancer Center Innsbruck, Medical University of Innsbruck, Innsbruck, Austria
| | - Sooryanarayana Varambally
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL
| | - Upender Manne
- Department of Pathology, University of Alabama at Birmingham, Birmingham, AL
- Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL
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Xu K, Wang T, Pan S, He J. The efficacy and toxicity of mirvetuximab soravtansine, a novel antibody-drug conjugate, in the treatment of advanced or recurrent ovarian cancer: a meta-analysis. Expert Rev Clin Pharmacol 2023; 16:1141-1152. [PMID: 37771164 DOI: 10.1080/17512433.2023.2262673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2023] [Accepted: 09/19/2023] [Indexed: 09/30/2023]
Abstract
INTRODUCTION This meta-analysis aims to systematically analyze the efficacy and toxicity of mirvetuximab soravtansine (MIRV) as second-line and above treatment for advanced or recurrent ovarian cancer. METHODS Candidate studies were identified in PubMed, Embase, Cochrane Library, CNKI, and Wanfang databases up to 1 May 2023. Objective response rate (ORR), progression-free survival (PFS), the incidence of adverse events (AEs), and incidence of grade ≥ 3 AEs were extracted and calculated by meta-analysis of merging ratios or mean to describe the efficacy and toxicity of MIRV. RESULTS Seven eligible prospective studies were included in this meta-analysis, including 605 patients with advanced ovarian cancer who received second-line or higher therapy. ORR of MIRV was 34.2% (95% confidence interval [CI] 25.0-43.5), and PFS was 5.82 months (95%CI 4.47-7.18). The overall incidence of AEs was 87.4% (95%CI 52.9-100.0) and the incidence of grade ≥ 3 AEs was 27.1% (95%CI 18.9-36.1). The most common AEs were vision blurring, nausea, and diarrhea, with incidence of 46.7% (39.6-53.8), 41.8% (34.0-49.9), and 41.3% (30.4-52.5), respectively. CONCLUSIONS MIRV has definite efficacy and good safety as a novel choice for second-line and above treatment of advanced or recurrent FRα positive ovarian cancer. This may have promising application in patients with platinum-resistant diseases. PROSPERO REGISTRATION NUMBER CRD42023428599.
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Affiliation(s)
- Ke Xu
- Clinical Medical College, Chengdu Medical College, Chengdu, Sichuan, China
- Department of Oncology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
| | - Tianlei Wang
- Clinical Medical College, Chengdu Medical College, Chengdu, Sichuan, China
| | - Shenbin Pan
- Clinical Medical College, Chengdu Medical College, Chengdu, Sichuan, China
| | - Jie He
- Clinical Medical College, Chengdu Medical College, Chengdu, Sichuan, China
- Department of Pulmonary and Critical Care Medicine, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
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Chang YL, Chou CH, Li YF, Huang LC, Kao Y, Hueng DY, Tsai CK. Antiproliferative and apoptotic effects of telmisartan in human glioma cells. Cancer Cell Int 2023; 23:111. [PMID: 37291545 DOI: 10.1186/s12935-023-02963-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Accepted: 06/05/2023] [Indexed: 06/10/2023] Open
Abstract
Glioblastoma is the most common primary central nervous system tumor in adults. Angiotensin II receptor blockers (ARBs) are broadly applied to treat hypertension. Moreover, research has revealed that ARBs have the capacity to suppress the growth of several cancer types. In this study, we assessed the effects of three ARBs with the ability to cross the blood brain barrier (telmisartan, valsartan and fimasartan) on cell proliferation in three glioblastoma multiforme (GBM) cell lines. Telmisartan markedly suppressed the proliferation, migration, and invasion of these three GBM cell lines. Microarray data analysis revealed that telmisartan regulates DNA replication, mismatch repair, and the cell cycle pathway in GBM cells. Furthermore, telmisartan induced G0/G1 phase arrest and apoptosis. The bioinformatic analysis and western blotting results provide evidence that SOX9 is a downstream target of telmisartan. Telmisartan also suppressed tumor growth in vivo in an orthotopic transplant mouse model. Therefore, telmisartan is a potential treatment for human GBM.
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Affiliation(s)
- Yung-Lung Chang
- Department of Biochemistry, National Defense Medical Center, Taipei, 11490, Taiwan
| | - Chung-Hsing Chou
- Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, No. 325, Sec. 2, Cheng-Gong Road, Taipei, 11490, Taiwan
| | - Yao-Feng Li
- Department of Pathology, Tri-Service General Hospital, National Defense Medical Center, Taipei, 11490, Taiwan
| | - Li-Chun Huang
- Department of Biochemistry, National Defense Medical Center, Taipei, 11490, Taiwan
| | - Ying Kao
- Division of Neurosurgery, Department of Surgery, Taipei City Hospital Zhongxing Branch, Taipei, Taiwan
| | - Dueng-Yuan Hueng
- Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei, 11490, Taiwan
| | - Chia-Kuang Tsai
- Department of Neurology, Tri-Service General Hospital, National Defense Medical Center, No. 325, Sec. 2, Cheng-Gong Road, Taipei, 11490, Taiwan.
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11
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Zhang H, Zhen S, Ding P, Tan B, Wang H, Liu W, Tian Y, Zhao Q. Screening of Differentially Expressed Genes Based on the ACRG Molecular Subtypes of Gastric Cancer and the Significance and Mechanism of AGTR1 Gene Expression. J Pers Med 2023; 13:jpm13030560. [PMID: 36983741 PMCID: PMC10055834 DOI: 10.3390/jpm13030560] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2023] [Revised: 03/15/2023] [Accepted: 03/16/2023] [Indexed: 03/30/2023] Open
Abstract
BACKGROUND The Asian Cancer Research Group (ACRG) classification is a molecular classification established based on the tissues of gastric cancer (GC) patients in Asia. Patients with different ACRG subtypes differ significantly with regard to treatment response and prognosis, which indicates that the ACRG molecular classification is more valuable than the traditional pathological classification. However, the specific differentially expressed genes (DEGs) and the value of the ACRG molecular subtypes of GC have not been studied in depth. METHODS Through the analysis of the GEO database, the DEGs in GC tissues of different ACRG molecular subtypes were investigated. The expression and mechanism of the screened angiotensin II receptor type 1 (AGTR1) gene were bioinformatically analyzed and experimentally verified. The role of AGTR1 in GC cells was mainly investigated using CCK-8, wound-healing, transwell invasion assays, qRT-PCR, and Western blotting. RESULTS The bioinformatics results showed the presence of multiple DEGs in GC tissues with different ACRG molecular subtypes. Certain DEGs in GC tissues of different ACRG molecular subtypes have prognostic significance. AGTR1 levels in tumor tissues were significantly higher than in paired paracancerous tissues. The prognosis of GC patients with high expression of AGTR1 was poor (p < 0.05). The AGTR1 gene in GC samples was associated with the expression of immune pathways and immune checkpoint genes. After modifying AGTR1 expression in cell lines, cells' proliferation, invasion, and migration abilities and the expression of related genes changed. CONCLUSIONS There were significant DEGs in GC tissues with different ACGR molecular types, among which the increased expression of AGTR1 was a molecular feature of MSS/EMT type gastric cancer. Further study found that AGTR1 was closely related to tumor immune infiltration and invasion and may be a new therapeutic target gene for gastric cancer.
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Affiliation(s)
- Haoran Zhang
- Second Department of Thoracic Surgery, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang 050011, China
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang 050011, China
| | - Shuman Zhen
- Second Department of Radiotherapy, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang 050011, China
| | - Pingan Ding
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang 050011, China
- Third Department of General Surgery, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang 050011, China
| | - Bibo Tan
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang 050011, China
- Third Department of General Surgery, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang 050011, China
| | - Hongyan Wang
- Second Department of Thoracic Surgery, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang 050011, China
| | - Wenbo Liu
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang 050011, China
- Third Department of General Surgery, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang 050011, China
| | - Yuan Tian
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang 050011, China
- Third Department of General Surgery, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang 050011, China
| | - Qun Zhao
- Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang 050011, China
- Third Department of General Surgery, The Fourth Affiliated Hospital of Hebei Medical University, Shijiazhuang 050011, China
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12
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Sehn F, Büttner H, Godau B, Müller M, Sarcan S, Offermann A, Perner S, Kramer MW, Merseburger AS, Roesch MC. The alternative renin-angiotensin-system (RAS) signalling pathway in prostate cancer and its link to the current COVID-19 pandemic. Mol Biol Rep 2023; 50:1809-1816. [PMID: 36478297 PMCID: PMC9734445 DOI: 10.1007/s11033-022-08087-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 11/03/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND The renin-angiotensin system is known to maintain blood pressure and body fluids. However, it has been found to consist of at least two major constituents, the classic and the alternative pathway, balancing and supporting each other's signalling in a very intricate way. Current research has shown that the renin-angiotensin system is involved in a broad range of biological processes and diseases, such as cancer and infectious diseases. METHODS AND RESULTS We conducted a literature review on the interaction of the renin-angiotensin system and prostate cancer and explored the research on the possible impact of the SARS-CoV-2 virus in this context. This review provides an update on contemporary knowledge into the alternative renin-angiotensin system, its role in cancer, specifically prostate cancer, and the implications of the current COVID-19 pandemic on cancer and cancer care. CONCLUSION In this work, we aim to demonstrate how shifting the RAS signalling pathway from the classic to the alternative axis seems to be a viable option in supporting treatment of specific cancers and at the same time demonstrating beneficial properties in supportive care. It however seems to be the case that the infection with SARS-CoV-2 and subsequent impairment of the renin-angiotensin-system could exhibit serious deleterious long-term effects even in oncology.
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Affiliation(s)
- Fabian Sehn
- Department of Urology, University Hospital Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
- Takeda Pharma Vertrieb GmbH und Co. KG, Jägerstrasse 27, 10117 Berlin, Germany
| | - Hartwig Büttner
- Takeda Pharma Vertrieb GmbH und Co. KG, Jägerstrasse 27, 10117 Berlin, Germany
| | - Beate Godau
- Department of Urology, University Hospital Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
| | - Marten Müller
- Department of Urology, University Hospital Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
| | - Semih Sarcan
- Department of Urology, University Hospital Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
| | - Anne Offermann
- Institute of Pathology, University Hospital Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
| | - Sven Perner
- Institute of Pathology, University Hospital Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
- Research Center Borstel, Leibniz Lung Center, Pathology, Parkallee 1-40, 23845 Borstel, Germany
| | - Mario W. Kramer
- Department of Urology, University Hospital Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
| | - Axel S. Merseburger
- Department of Urology, University Hospital Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
| | - Marie C. Roesch
- Department of Urology, University Hospital Schleswig-Holstein, Campus Lübeck, Ratzeburger Allee 160, 23538 Lübeck, Germany
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Roundhill EA, Pantziarka P, Liddle DE, Shaw LA, Albadrani G, Burchill SA. Exploiting the Stemness and Chemoresistance Transcriptome of Ewing Sarcoma to Identify Candidate Therapeutic Targets and Drug-Repurposing Candidates. Cancers (Basel) 2023; 15:cancers15030769. [PMID: 36765727 PMCID: PMC9913297 DOI: 10.3390/cancers15030769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2022] [Revised: 01/08/2023] [Accepted: 01/17/2023] [Indexed: 01/28/2023] Open
Abstract
Outcomes for most patients with Ewing sarcoma (ES) have remained unchanged for the last 30 years, emphasising the need for more effective and tolerable treatments. We have hypothesised that using small-molecule inhibitors to kill the self-renewing chemotherapy-resistant cells (Ewing sarcoma cancer stem-like cells; ES-CSCs) responsible for progression and relapse could improve outcomes and minimise treatment-induced morbidities. For the first time, we demonstrate that ABCG1, a potential oncogene in some cancers, is highly expressed in ES-CSCs independently of CD133. Using functional models, transcriptomics and a bespoke in silico drug-repurposing pipeline, we have prioritised a group of tractable small-molecule inhibitors for further preclinical studies. Consistent with the cellular origin of ES, 21 candidate molecular targets of pluripotency, stemness and chemoresistance were identified. Small-molecule inhibitors to 13 of the 21 molecular targets (62%) were identified. POU5F1/OCT4 was the most promising new therapeutic target in Ewing sarcoma, interacting with 10 of the 21 prioritised molecular targets and meriting further study. The majority of small-molecule inhibitors (72%) target one of two drug efflux proteins, p-glycoprotein (n = 168) or MRP1 (n = 13). In summary, we have identified a novel cell surface marker of ES-CSCs and cancer/non-cancer drugs to targets expressed by these cells that are worthy of further preclinical evaluation. If effective in preclinical models, these drugs and drug combinations might be repurposed for clinical evaluation in patients with ES.
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Affiliation(s)
- Elizabeth Ann Roundhill
- Children’s Cancer Research Group, Leeds Institute of Medical Research, St James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK
- Correspondence: (E.A.R.); (S.A.B.)
| | - Pan Pantziarka
- Anticancer Fund, Brusselsesteenweg 11, 1860 Meise, Belgium
| | - Danielle E. Liddle
- Children’s Cancer Research Group, Leeds Institute of Medical Research, St James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK
| | - Lucy A. Shaw
- Children’s Cancer Research Group, Leeds Institute of Medical Research, St James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK
| | - Ghadeer Albadrani
- Children’s Cancer Research Group, Leeds Institute of Medical Research, St James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK
| | - Susan Ann Burchill
- Children’s Cancer Research Group, Leeds Institute of Medical Research, St James’s University Hospital, Beckett Street, Leeds LS9 7TF, UK
- Correspondence: (E.A.R.); (S.A.B.)
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Yang K, Wang X, Song C, He Z, Wang R, Xu Y, Jiang G, Wan Y, Mei J, Mao W. The role of lipid metabolic reprogramming in tumor microenvironment. Theranostics 2023; 13:1774-1808. [PMID: 37064872 PMCID: PMC10091885 DOI: 10.7150/thno.82920] [Citation(s) in RCA: 57] [Impact Index Per Article: 28.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2023] [Accepted: 03/07/2023] [Indexed: 04/18/2023] Open
Abstract
Metabolic reprogramming is one of the most important hallmarks of malignant tumors. Specifically, lipid metabolic reprogramming has marked impacts on cancer progression and therapeutic response by remodeling the tumor microenvironment (TME). In the past few decades, immunotherapy has revolutionized the treatment landscape for advanced cancers. Lipid metabolic reprogramming plays pivotal role in regulating the immune microenvironment and response to cancer immunotherapy. Here, we systematically reviewed the characteristics, mechanism, and role of lipid metabolic reprogramming in tumor and immune cells in the TME, appraised the effects of various cell death modes (specifically ferroptosis) on lipid metabolism, and summarized the antitumor therapies targeting lipid metabolism. Overall, lipid metabolic reprogramming has profound effects on cancer immunotherapy by regulating the immune microenvironment; therefore, targeting lipid metabolic reprogramming may lead to the development of innovative clinical applications including sensitizing immunotherapy.
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Affiliation(s)
- Kai Yang
- Department of Thoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
- Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Nanjing, 210029, China
| | - Xiaokun Wang
- Department of Thoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Chenghu Song
- Department of Thoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Zhao He
- Department of Thoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Ruixin Wang
- Department of Thoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Yongrui Xu
- Department of Thoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Guanyu Jiang
- Department of Thoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
| | - Yuan Wan
- The Pq Laboratory of BiomeDx/Rx, Department of Biomedical Engineering, Binghamton University, Binghamton 13850, USA
- ✉ Corresponding authors: Wenjun Mao, M.D., Department of Cardiothoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, No. 299 Qingyang Rd., Wuxi, 214023, China. E-mail: . Jie Mei, M.D., Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, No. 299 Qingyang Rd., Wuxi, 214023, China. E-mail: . Yuan Wan, Ph.D., The Pq Laboratory of BiomeDx/Rx, Department of Biomedical Engineering, Binghamton University, No. 65 Murray Hill Rd., Binghamton, 13850, USA. E-mail:
| | - Jie Mei
- Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Nanjing, 210029, China
- ✉ Corresponding authors: Wenjun Mao, M.D., Department of Cardiothoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, No. 299 Qingyang Rd., Wuxi, 214023, China. E-mail: . Jie Mei, M.D., Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, No. 299 Qingyang Rd., Wuxi, 214023, China. E-mail: . Yuan Wan, Ph.D., The Pq Laboratory of BiomeDx/Rx, Department of Biomedical Engineering, Binghamton University, No. 65 Murray Hill Rd., Binghamton, 13850, USA. E-mail:
| | - Wenjun Mao
- Department of Thoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, Wuxi, 214023, China
- ✉ Corresponding authors: Wenjun Mao, M.D., Department of Cardiothoracic Surgery, The Affiliated Wuxi People's Hospital of Nanjing Medical University, No. 299 Qingyang Rd., Wuxi, 214023, China. E-mail: . Jie Mei, M.D., Department of Oncology, The Affiliated Wuxi People's Hospital of Nanjing Medical University, No. 299 Qingyang Rd., Wuxi, 214023, China. E-mail: . Yuan Wan, Ph.D., The Pq Laboratory of BiomeDx/Rx, Department of Biomedical Engineering, Binghamton University, No. 65 Murray Hill Rd., Binghamton, 13850, USA. E-mail:
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15
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Huang X, Li XY, Shan WL, Chen Y, Zhu Q, Xia BR. Targeted therapy and immunotherapy: Diamonds in the rough in the treatment of epithelial ovarian cancer. Front Pharmacol 2023; 14:1131342. [PMID: 37033645 PMCID: PMC10080064 DOI: 10.3389/fphar.2023.1131342] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2022] [Accepted: 02/21/2023] [Indexed: 04/11/2023] Open
Abstract
Currently, for ovarian cancer, which has the highest mortality rate among all gynecological cancers, the standard treatment protocol is initial tumor cytoreductive surgery followed by platinum-based combination chemotherapy. Although the survival rate after standard treatment has improved, the therapeutic effect of traditional chemotherapy is very limited due to problems such as resistance to platinum-based drugs and recurrence. With the advent of the precision medicine era, molecular targeted therapy has gradually entered clinicians' view, and individualized precision therapy has been realized, surpassing the limitations of traditional therapy. The detection of genetic mutations affecting treatment, especially breast cancer susceptibility gene (BRCA) mutations and mutations of other homologous recombination repair defect (HRD) genes, can guide the targeted drug treatment of patients, effectively improve the treatment effect and achieve a better patient prognosis. This article reviews different sites and pathways of targeted therapy, including angiogenesis, cell cycle and DNA repair, and immune and metabolic pathways, and the latest research progress from preclinical and clinical trials related to ovarian cancer therapy.
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Affiliation(s)
- Xu Huang
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Bengbu Medical College Bengbu, Anhui, China
| | - Xiao-Yu Li
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
- Bengbu Medical College Bengbu, Anhui, China
| | - Wu-Lin Shan
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Yao Chen
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Anhui Provincial Cancer Hospital, Hefei, Anhui, China
| | - Qi Zhu
- The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, China
| | - Bai-Rong Xia
- Bengbu Medical College Bengbu, Anhui, China
- *Correspondence: Bai-Rong Xia,
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Kashyap MK, Bhat A, Janjua D, Rao R, Thakur K, Chhokar A, Aggarwal N, Yadav J, Tripathi T, Chaudhary A, Senrung A, Chandra Bharti A. Role of angiotensin in different malignancies. ANGIOTENSIN 2023:505-544. [DOI: 10.1016/b978-0-323-99618-1.00019-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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17
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Singla RK, Sharma P, Kumar D, Gautam RK, Goyal R, Tsagkaris C, Dubey AK, Bansal H, Sharma R, Shen B. The role of nanomaterials in enhancing natural product translational potential and modulating endoplasmic reticulum stress in the treatment of ovarian cancer. Front Pharmacol 2022; 13:987088. [PMID: 36386196 PMCID: PMC9643842 DOI: 10.3389/fphar.2022.987088] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Accepted: 10/03/2022] [Indexed: 10/21/2023] Open
Abstract
Ovarian cancer, and particularly its most frequent type, epithelial ovarian carcinoma, constitutes one of the most dangerous malignant tumors among females. Substantial evidence has described the potential of phytochemicals against ovarian cancer. The effect of natural compounds on endoplasmic reticulum (ER) stress is of great relevance in this regard. In ovarian cancer, the accumulation of misfolded proteins in the ER lumen results in decompensated ER stress. This leads to deregulation in the physiological processes for the posttranslational modification of proteins, jeopardizes cellular homeostasis, and increases apoptotic signaling. Several metabolites and metabolite extracts of phytochemical origin have been studied in the context of ER stress in ovarian cancer. Resveratrol, quercetin, curcumin, fucosterol, cleistopholine, fucoidan, and epicatechin gallate, among others, have shown inhibitory potential against ER stress. The chemical structure of each compound plays an important role concerning its pharmacodynamics, pharmacokinetics, and overall effectiveness. Studying and cross-comparing the chemical features that render different phytochemicals effective in eliciting particular anti-ER stress actions can help improve drug design or develop multipotent combination regimens. Many studies have also investigated the properties of formulations such as nanoparticles, niosomes, liposomes, and intravenous hydrogel based on curcumin and quercetin along with some other phytomolecules in ovarian cancer. Overall, the potential of phytochemicals in targeting genetic mechanisms of ovarian cancer warrants further translational and clinical investigation.
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Affiliation(s)
- Rajeev K. Singla
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
- School of Pharmaceutical Sciences, Lovely Professional University, Phagwara, India
| | - Pooja Sharma
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, Patiala, India
- Khalsa College of Pharmacy, Amritsar, India
| | - Dinesh Kumar
- Chitkara University School of Pharmacy, Chitkara University, Himachal Pradesh, India
| | - Rupesh K. Gautam
- Department of Pharmacology, Indore Institute of Pharmacy, IIST Campus, Opposite IIM Indore, Indore, India
| | - Rajat Goyal
- MM College of Pharmacy, Maharishi Markandeshwar (Deemed to be University), Mullana-Ambala, India
| | | | | | - Himangini Bansal
- Delhi Institute of Pharmaceutical Sciences and Research, New Delhi, India
| | - Rohit Sharma
- Department of Rasa Shastra and Bhaishajya Kalpana, Faculty of Ayurveda, Institute of Medical Sciences, BHU, Varanasi, India
| | - Bairong Shen
- Institutes for Systems Genetics, Frontiers Science Center for Disease-Related Molecular Network, West China Hospital, Sichuan University, Chengdu, China
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18
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Xiong Y, Ke R, Zhang Q, Lan W, Yuan W, Chan KNI, Roussel T, Jiang Y, Wu J, Liu S, Wong AST, Shim JS, Zhang X, Xie R, Dusetti N, Iovanna J, Habib N, Peng L, Lee LTO. Small Activating RNA Modulation of the G Protein-Coupled Receptor for Cancer Treatment. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2200562. [PMID: 35712764 PMCID: PMC9475523 DOI: 10.1002/advs.202200562] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Revised: 05/23/2022] [Indexed: 06/15/2023]
Abstract
G protein-coupled receptors (GPCRs) are the most common and important drug targets. However, >70% of GPCRs are undruggable or difficult to target using conventional chemical agonists/antagonists. Small nucleic acid molecules, which can sequence-specifically modulate any gene, offer a unique opportunity to effectively expand drug targets, especially those that are undruggable or difficult to address, such as GPCRs. Here, the authors report for the first time that small activating RNAs (saRNAs) effectively modulate a GPCR for cancer treatment. Specifically, saRNAs promoting the expression of Mas receptor (MAS1), a GPCR that counteracts the classical angiotensin II pathway in cancer cell proliferation and migration, are identified. These saRNAs, delivered by an amphiphilic dendrimer vector, enhance MAS1 expression, counteracting the angiotensin II/angiotensin II Receptor Type 1 axis, and leading to significant suppression of tumorigenesis and the inhibition of tumor progression of multiple cancers in tumor-xenografted mouse models and patient-derived tumor models. This study provides not only a new strategy for cancer therapy by targeting the renin-angiotensin system, but also a new avenue to modulate GPCR signaling by RNA activation.
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Affiliation(s)
- Yunfang Xiong
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
| | - Ran Ke
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
| | - Qingyu Zhang
- Department of Obstetrics and GynaecologyAffiliated Hospital of Guangdong Medical UniversityZhanjiangGuangdong524001China
| | - Wenjun Lan
- Aix Marseille UniversitéCNRSCentre Interdisciplinaire de Nanoscience de Marseille (UMR 7325)Equipe Labellisée Ligue Contre le CancerMarseille13288France
- Centre de Recherche en Cancérologie de Marseille (CRCM)INSERM U1068CNRSAix‐Marseille Université and Institut Paoli‐CalmettesMarseille13288France
| | - Wanjun Yuan
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
| | - Karol Nga Ieng Chan
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
| | - Tom Roussel
- Aix Marseille UniversitéCNRSCentre Interdisciplinaire de Nanoscience de Marseille (UMR 7325)Equipe Labellisée Ligue Contre le CancerMarseille13288France
| | - Yifan Jiang
- Aix Marseille UniversitéCNRSCentre Interdisciplinaire de Nanoscience de Marseille (UMR 7325)Equipe Labellisée Ligue Contre le CancerMarseille13288France
| | - Jing Wu
- Aix Marseille UniversitéCNRSCentre Interdisciplinaire de Nanoscience de Marseille (UMR 7325)Equipe Labellisée Ligue Contre le CancerMarseille13288France
| | - Shuai Liu
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
| | - Alice Sze Tsai Wong
- School of Biological SciencesThe University of Hong KongPokfulam RoadHong KongChina
| | - Joong Sup Shim
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
- MOE Frontiers Science Center for Precision OncologyUniversity of MacauTaipaMacau999078China
| | - Xuanjun Zhang
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
- MOE Frontiers Science Center for Precision OncologyUniversity of MacauTaipaMacau999078China
| | - Ruiyu Xie
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
- MOE Frontiers Science Center for Precision OncologyUniversity of MacauTaipaMacau999078China
| | - Nelson Dusetti
- Centre de Recherche en Cancérologie de Marseille (CRCM)INSERM U1068CNRSAix‐Marseille Université and Institut Paoli‐CalmettesMarseille13288France
| | - Juan Iovanna
- Centre de Recherche en Cancérologie de Marseille (CRCM)INSERM U1068CNRSAix‐Marseille Université and Institut Paoli‐CalmettesMarseille13288France
| | - Nagy Habib
- Department of Surgery and CancerImperial College LondonLondonW12 0NNUK
- MiNA Therapeutics, Translation & Innovation Hub80 Wood LaneLondonW12 0BZUK
| | - Ling Peng
- Aix Marseille UniversitéCNRSCentre Interdisciplinaire de Nanoscience de Marseille (UMR 7325)Equipe Labellisée Ligue Contre le CancerMarseille13288France
| | - Leo Tsz On Lee
- Cancer CentreFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
- MOE Frontiers Science Center for Precision OncologyUniversity of MacauTaipaMacau999078China
- Centre of Reproduction, Development, and AgingFaculty of Health SciencesUniversity of MacauTaipaMacau999078China
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Kawata M, Kondo J, Onuma K, Ito Y, Yokoi T, Hamanishi J, Mandai M, Kimura T, Inoue M. Polarity switching of ovarian cancer cell clusters via SRC family kinase is involved in the peritoneal dissemination. Cancer Sci 2022; 113:3437-3448. [PMID: 35848881 PMCID: PMC9530866 DOI: 10.1111/cas.15493] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Revised: 07/04/2022] [Accepted: 07/11/2022] [Indexed: 11/30/2022] Open
Abstract
Peritoneal dissemination is a predominant pattern of metastasis in patients with advanced ovarian cancer. Despite recent progress in the management strategy, peritoneal dissemination remains a determinant of poor ovarian cancer prognosis. Using various histological types of patient‐derived ovarian cancer organoids, the roles of the apicobasal polarity of ovarian cancer cell clusters in peritoneal dissemination were studied. First, it was found that both ovarian cancer tissues and ovarian organoids showed apicobasal polarity, where zonula occludens‐1 (ZO‐1) and integrin beta 4 (ITGB4) served as markers for apical and basal sides, respectively. The organoids in suspension culture, as a model of cancer cell cluster floating in ascites, showed apical‐out/basal‐in polarity status, while once embedded in extracellular matrix (ECM), the organoids switched their polarity to apical‐in/basal‐out. This polarity switch was accompanied by the SRC kinase family (SFK) phosphorylation and was inhibited by SFK inhibitors. SFK inhibitors abrogated the adherence of the organoids onto the ECM‐coated plastic surface. When the organoids were seeded on a mesothelial cell layer, they cleared and invaded mesothelial cells. In vivo, dasatinib, an SFK inhibitor, suppressed peritoneal dissemination of ovarian cancer organoids in immunodeficient mice. These results suggest SFK‐mediated polarity switching is involved in peritoneal metastasis. Polarity switching would be a potential therapeutic target for suppressing peritoneal dissemination in ovarian cancer.
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Affiliation(s)
- Mayuko Kawata
- Department of Clinical Bioresource Research and Development, Kyoto University Graduate School of Medicine.,Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine
| | - Jumpei Kondo
- Department of Clinical Bioresource Research and Development, Kyoto University Graduate School of Medicine.,Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine.,Department of Molecular Biochemistry and Clinical Investigation, Division of Health Science, Osaka University Graduate School of Medicine, 1-7 Yamadaoka, Suita City, Osaka, Japan
| | - Kunishige Onuma
- Department of Clinical Bioresource Research and Development, Kyoto University Graduate School of Medicine
| | - Yu Ito
- Department of Clinical Bioresource Research and Development, Kyoto University Graduate School of Medicine.,Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine
| | - Takeshi Yokoi
- Department of Obstetrics and Gynecology, Kaizuka, City Hospital
| | - Junzo Hamanishi
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine
| | - Masaki Mandai
- Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine
| | - Tadashi Kimura
- Department of Obstetrics and Gynecology, Osaka University Graduate School of Medicine
| | - Masahiro Inoue
- Department of Clinical Bioresource Research and Development, Kyoto University Graduate School of Medicine
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20
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Wang H, Cui Y, Gong H, Xu J, Huang S, Tang A. Suppression of AGTR1 Induces Cellular Senescence in Hepatocellular Carcinoma Through Inactivating ERK Signaling. Front Bioeng Biotechnol 2022; 10:929979. [PMID: 35910032 PMCID: PMC9326343 DOI: 10.3389/fbioe.2022.929979] [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: 04/27/2022] [Accepted: 06/06/2022] [Indexed: 11/13/2022] Open
Abstract
Objective: Cellular senescence is an effective barrier against tumorigenesis. Hence, it is of significance to characterize key features of cellular senescence and the induction of senescence in hepatocellular carcinoma (HCC) cells via pharmacological interventions. Our study determined the biological roles as well as mechanisms of angiotensin II type I receptor (AGTR1) on cellular senescence in HCC.Methods: Lentivirus vector-mediated overexpression or knockdown of AGTR1 was conducted in HCC cells, respectively. A volume of 8 μM sorafenib was used to induce cellular senescence, and ERK was activated by 30 ng/ml ERK agonist EGF. Proliferation was evaluated via clone formation assay. HCC cell senescence was examined by flow cytometry for cell cycle, senescence-associated β-galactosidase (SA-β-gal) staining, and senescence-associated heterochromatin foci (SAHF) analysis. AGTR1, p53, p21, extracellular signal-regulated kinase (ERK), and p-ERK expression were assessed through Western blot or immunofluorescence.Results: AGTR1-knockout HCC cells displayed the attenuated proliferative capacity, G2-M phase arrest, increased expression of p53 and p21, and elevated percentages of SA-β-gal- and SAHF-positive cells. In sorafenib-exposed HCC cells, overexpressed AGTR1 enhanced the proliferative capacity and alleviated G2-M phase arrest as well as decreased p53 and p21 expression and the proportions of SA-β-gal- and SAHF-positive cells. Moreover, AGTR1 knockdown attenuated the activity of p-ERK in HCC cells, and ERK agonist ameliorated AGTR1 knockdown-induced cellular senescence.Conclusion: This study demonstrates that suppression of AGTR1 induces cellular senescence in HCC through inactivating ERK signaling. The significant synergistic effect of AGTR1 suppression and sorafenib might represent a potential combination therapy for HCC.
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Affiliation(s)
- Houhong Wang
- Department of General Surgery, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, China
| | - Yayun Cui
- Department of Cancer Radiotherapy, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, (Anhui Provincial Cancer Hospital), University of Science and Technology of China, Hefei, China
| | - Huihui Gong
- Faculty of Health and Life Sciences, Oxford Brookes University, Oxford, United Kingdom
| | - Jianguo Xu
- Department of General Surgery, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, China
| | - Shuqin Huang
- Department of General Surgery, The Affiliated Bozhou Hospital of Anhui Medical University, Bozhou, China
| | - Amao Tang
- Department of Gastroenterology, The Affiliated Hangzhou First People’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
- *Correspondence: Amao Tang,
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21
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Salinas-Vera YM, Valdés J, Pérez-Navarro Y, Mandujano-Lazaro G, Marchat LA, Ramos-Payán R, Nuñez-Olvera SI, Pérez-Plascencia C, López-Camarillo C. Three-Dimensional 3D Culture Models in Gynecological and Breast Cancer Research. Front Oncol 2022; 12:826113. [PMID: 35692756 PMCID: PMC9177953 DOI: 10.3389/fonc.2022.826113] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Accepted: 04/20/2022] [Indexed: 12/12/2022] Open
Abstract
Traditional two-dimensional (2D) monolayer cell cultures have long been the gold standard for cancer biology research. However, their ability to accurately reflect the molecular mechanisms of tumors occurring in vivo is limited. Recent development of three-dimensional (3D) cell culture models facilitate the possibility to better recapitulate several of the biological and molecular characteristics of tumors in vivo, such as cancer cells heterogeneity, cell-extracellular matrix interactions, development of a hypoxic microenvironment, signaling pathway activities depending on contacts with extracellular matrix, differential growth kinetics, more accurate drugs response, and specific gene expression and epigenetic patterns. In this review, we discuss the utilization of different types of 3D culture models including spheroids, organotypic models and patient-derived organoids in gynecologic cancers research, as well as its potential applications in oncological research mainly for screening drugs with major physiological and clinical relevance. Moreover, microRNAs regulation of cancer hallmarks in 3D cell cultures from different types of cancers is discussed.
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Affiliation(s)
- Yarely M. Salinas-Vera
- Departamento de Bioquímica, Centro de Investigación de Estudios Avanzados (CINVESTAV-IPN), Ciudad de Mexico, Mexico
| | - Jesús Valdés
- Departamento de Bioquímica, Centro de Investigación de Estudios Avanzados (CINVESTAV-IPN), Ciudad de Mexico, Mexico
| | - Yussel Pérez-Navarro
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de Mexico, Ciudad de Mexico, Mexico
| | - Gilberto Mandujano-Lazaro
- Programa en Biomedicina Molecular y Red de Biotecnología, Instituto Politécnico Nacional, Ciudad de Mexico, Mexico
| | - Laurence A. Marchat
- Programa en Biomedicina Molecular y Red de Biotecnología, Instituto Politécnico Nacional, Ciudad de Mexico, Mexico
| | - Rosalio Ramos-Payán
- Facultad de Ciencias Químico Biológicas, Universidad Autónoma de Sinaloa, Culiacán Sinaloa, Mexico
| | - Stephanie I. Nuñez-Olvera
- Departamento de Biología Celular y Fisiología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad de México, Mexico
| | | | - César López-Camarillo
- Posgrado en Ciencias Genómicas, Universidad Autónoma de la Ciudad de Mexico, Ciudad de Mexico, Mexico
- *Correspondence: César López-Camarillo, ; orcid.org/0000-0002-9417-2609
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22
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Balasundaram A, Udhaya Kumar S, George Priya Doss C. A computational model revealing the immune-related hub genes and key pathways involved in rheumatoid arthritis (RA). ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2022; 129:247-273. [PMID: 35305721 DOI: 10.1016/bs.apcsb.2021.11.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Rheumatoid arthritis (RA) has one of the highest disability rates among inflammatory joint disorders. However, the reason and possible molecular events are still unclear. There are various treatment options available, but no complete cure. To obtain early diagnosis and successful medication in RA, it is necessary to explore gene susceptibility and pathogenic factors. The main intend of our work is to explore the immune-related hub genes with similar functions that are differentially expressed in RA patients. Three datasets such as GSE21959, GSE55457, and GSE77298, were taken to analyze the differently expressed genes (DEGs) among 55 RA and 33 control samples. We obtained 331 upregulated and 275 downregulated DEGs from three Gene Expression Omnibus (GEO) datasets using the R package. Furthermore, a protein-protein interaction network was built for upregulated and downregulated DEGs using Cytoscape. Subsequently, MCODE analysis was performed and obtained the top two modules in each DEG's upregulated and downregulated protein-protein interactions (PPIs) network. CytoNCA and cytoHubba were performed and identified overlapping DEGs. In addition, we narrowed down DEGs by filtering with immune-related genes and identified DE-IRGs. Gene ontology (GO) and KEGG pathway analysis in upregulated and downregulated DEGs were executed with the DAVID platform. Our study obtained the nine most significant DE-IRGs in RA such as CXCR4, CDK1, BUB1, BIRC5, AGTR1, EGFR, EDNRB, KALRN, and GHSR. Among them, CXCR4, CDK1, BUB1, and BIRC5 are overexpressed in RA and may contribute to the pathophysiology of the disease. Similarly, AGTR1, EGFR, EDNRB, KALRN, and GHSR are all low expressed in RA and may have a contribution to pathogenesis. GO, KEGG functional enrichment, and GeneMANIA showed that the dysregulated process of DE-IRGs causes RA development and progression. These findings may be helpful in future studies in RA diagnosis and therapy.
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Affiliation(s)
- Ambritha Balasundaram
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, TN, India
| | - S Udhaya Kumar
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, TN, India
| | - C George Priya Doss
- School of Biosciences and Technology, Vellore Institute of Technology, Vellore, TN, India.
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23
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Wang SY, Hu QC, Wu T, Xia J, Tao XA, Cheng B. Abnormal lipid synthesis as a therapeutic target for cancer stem cells. World J Stem Cells 2022; 14:146-162. [PMID: 35432735 PMCID: PMC8963380 DOI: 10.4252/wjsc.v14.i2.146] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 05/19/2021] [Accepted: 02/20/2022] [Indexed: 02/06/2023] Open
Abstract
Cancer stem cells (CSCs) comprise a subpopulation of cancer cells with stem cell properties, which exhibit the characteristics of high tumorigenicity, self-renewal, and tumor initiation and are associated with the occurrence, metastasis, therapy resistance, and relapse of cancer. Compared with differentiated cells, CSCs have unique metabolic characteristics, and metabolic reprogramming contributes to the self-renewal and maintenance of stem cells. It has been reported that CSCs are highly dependent on lipid metabolism to maintain stemness and satisfy the requirements of biosynthesis and energy metabolism. In this review, we demonstrate that lipid anabolism alterations promote the survival of CSCs, including de novo lipogenesis, lipid desaturation, and cholesterol synthesis. In addition, we also emphasize the molecular mechanism underlying the relationship between lipid synthesis and stem cell survival, the signal trans-duction pathways involved, and the application prospect of lipid synthesis reprogramming in CSC therapy. It is demonstrated that the dependence on lipid synthesis makes targeting of lipid synthesis metabolism a promising therapeutic strategy for eliminating CSCs. Targeting key molecules in lipid synthesis will play an important role in anti-CSC therapy.
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Affiliation(s)
- Si-Yu Wang
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Qin-Chao Hu
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Tong Wu
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Juan Xia
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Xiao-An Tao
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
| | - Bin Cheng
- Department of Oral Medicine, Hospital of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
- Guangdong Provincial Key Laboratory of Stomatology, Guanghua School of Stomatology, Sun Yat-sen University, Guangzhou 510000, Guangdong Province, China
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24
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Liu Y, Hao H, Lan T, Jia R, Cao M, Zhou L, Zhao Z, Pan W. Physiological and pathological roles of Ang II and Ang- (1-7) in the female reproductive system. Front Endocrinol (Lausanne) 2022; 13:1080285. [PMID: 36619582 PMCID: PMC9817105 DOI: 10.3389/fendo.2022.1080285] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 12/05/2022] [Indexed: 12/25/2022] Open
Abstract
The local Renin-Angiotensin System (RAS) has been demonstrated to exist in a wide range of tissues and organs, In the female reproductive system, it is mainly found in the ovary, uterus and placenta. The RAS system is made up of a series of active substances and enzymes, in addition to the circulating endocrine renin-angiotensin system. The active peptides Angiotensin II (Ang II) and Angiotensin (1-7) (Ang-(1-7)), in particular, appear to have distinct activities in the local RAS system, which also controls blood pressure and electrolytes. Therefore, in addition to these features, angiotensin and its receptors in the reproductive system seemingly get involved in reproductive processes, such as follicle growth and development, as well as physiological functions of the placenta and uterus. In addition, changes in local RAS components may induce reproductive diseases as well as pathological states such as cancer. In most tissues, Ang II and Ang- (1-7) seem to maintain antagonistic effects, but this conclusion is not always true in the reproductive system, where they play similar functions in some physiological and pathological roles. This review investigated how Ang II, Ang- (1-7) and their receptors were expressed, localized, and active in the female reproductive system. This review also summarized their effects on follicle development, uterine and placental physiological functions. The changes of local RAS components in a series of reproductive system diseases including infertility related diseases and cancer and their influence on the occurrence and development of diseases were elucidated. This article reviews the physiological and pathological roles of Ang II and Ang- (1-7) in female reproductive system,a very intricate system of tissue factors that operate as agonists and antagonists was found. Besides, the development of novel therapeutic strategies targeting components of this system may be a research direction in future.
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Affiliation(s)
- Yuanyuan Liu
- Department of Reproductive Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Haomeng Hao
- Department of Reproductive Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Tingting Lan
- Department of Reproductive Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Rui Jia
- Department of Reproductive Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, China
- Shenzhen Key Laboratory of Reproductive Immunology for Peri-Implantation, Shenzhen Zhongshan Institute for Reproduction and Genetics, Shenzhen Zhongshan Urology Hospital, Shenzhen, Guangdong, China
| | - Mingya Cao
- Department of Reproductive Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Liang Zhou
- Department of Reproductive Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, China
| | - Zhiming Zhao
- Department of Reproductive Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, China
- *Correspondence: Wensen Pan, ; Zhiming Zhao,
| | - Wensen Pan
- Second Department of Respiratory and Critical Care Medicine, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- *Correspondence: Wensen Pan, ; Zhiming Zhao,
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25
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Domińska K, Urbanek KA, Kowalska K, Habrowska-Górczyńska DE, Kozieł MJ, Ochędalski T, Piastowska-Ciesielska AW. The Influence of Angiotensin Peptides on Survival and Motility of Human High-Grade Serous Ovarian Cancer Cells in Serum Starvation Conditions. Int J Mol Sci 2021; 23:52. [PMID: 35008474 PMCID: PMC8744539 DOI: 10.3390/ijms23010052] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/14/2021] [Accepted: 12/17/2021] [Indexed: 11/21/2022] Open
Abstract
High-grade serous ovarian carcinoma (HGSOC) is the most frequent and malignant form of ovarian cancer. A local renin-angiotensin system (RAS) has been found in the ovary, and changes in selected components of this system were observed in pathological states and also in ovarian cancer. In the present study, we examined the effect of three peptides, Ang-(1-7), Ang-(1-9) and Ang-(3-7), on proliferation and motility of the OVPA8 cell line, a new well-defined and preclinical model of HGSOC. We confirmed the presence of mRNA for all angiotensin receptors in the tested cells. Furthermore, our findings indicate that all tested angiotensin peptides increased the metabolic serum in the medium by activation of cell defense mechanisms such as nuclear factor kappaB signaling pathway andapoptosis. Moreover, tested angiotensin peptides intensified serum starvation-induced cell cycle arrest at the G0/G1 phase. In the case of Ang-(3-7), a significant decrease in the number of Ki67 positive cells (Ki67+) and reduced percentage of activated ERK1/2 levels in ovarian cancer cells were additionally reported. The angiotensin-induced effect of the accumulation of cells in the G0/G1 phase was not observed in OVPA8 cells growing on the medium with 10% FBS. Moreover, in the case of Ang-(3-7), the tendency was quite the opposite. Ang-(1-7) but not Ang-(1-9) or Ang-(3-7) increased the mobility of reluctant-to-migrate OVAP8 cells cultured in the serum-free medium. In any cases, the changes in the expression of VIM and HIF1A gene, associated with epithelial-mesenchymal transition (EMT), were not observed. In conclusion, we speculate that the adaptation to starvation in nutrient-deprived tumors can be modulated by peptides from the renin-angiotensin system. The influence of angiotensin peptides on cancer cells is highly dependent on the availability of growth factors and nutrients.
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Affiliation(s)
- Kamila Domińska
- Department of Comparative Endocrinology, Medical University of Lodz, Zeligowskiego 7/9, 90-752 Lodz, Poland;
| | - Kinga Anna Urbanek
- Department of Cell Cultures and Genomic Analysis, Medical University of Lodz, Zeligowskiego 7/9, 90-752 Lodz, Poland; (K.A.U.); (K.K.); (D.E.H.-G.); (M.J.K.); (A.W.P.-C.)
| | - Karolina Kowalska
- Department of Cell Cultures and Genomic Analysis, Medical University of Lodz, Zeligowskiego 7/9, 90-752 Lodz, Poland; (K.A.U.); (K.K.); (D.E.H.-G.); (M.J.K.); (A.W.P.-C.)
| | - Dominika Ewa Habrowska-Górczyńska
- Department of Cell Cultures and Genomic Analysis, Medical University of Lodz, Zeligowskiego 7/9, 90-752 Lodz, Poland; (K.A.U.); (K.K.); (D.E.H.-G.); (M.J.K.); (A.W.P.-C.)
| | - Marta Justyna Kozieł
- Department of Cell Cultures and Genomic Analysis, Medical University of Lodz, Zeligowskiego 7/9, 90-752 Lodz, Poland; (K.A.U.); (K.K.); (D.E.H.-G.); (M.J.K.); (A.W.P.-C.)
| | - Tomasz Ochędalski
- Department of Comparative Endocrinology, Medical University of Lodz, Zeligowskiego 7/9, 90-752 Lodz, Poland;
| | - Agnieszka Wanda Piastowska-Ciesielska
- Department of Cell Cultures and Genomic Analysis, Medical University of Lodz, Zeligowskiego 7/9, 90-752 Lodz, Poland; (K.A.U.); (K.K.); (D.E.H.-G.); (M.J.K.); (A.W.P.-C.)
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26
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Rajak P, Roy S, Dutta M, Podder S, Sarkar S, Ganguly A, Mandi M, Khatun S. Understanding the cross-talk between mediators of infertility and COVID-19. Reprod Biol 2021; 21:100559. [PMID: 34547545 PMCID: PMC8407955 DOI: 10.1016/j.repbio.2021.100559] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2021] [Revised: 08/27/2021] [Accepted: 08/29/2021] [Indexed: 12/13/2022]
Abstract
COVID-19 is the ongoing health emergency affecting individuals of all ages around the globe. Initially, the infection was reported to affect pulmonary structures. However, recent studies have delineated the impacts of COVID-19 on the reproductive system of both men and women. Hence, the present review aims to shed light on the distribution of SARS-CoV-2 entry factors in various reproductive organs. In addition, impacts of COVID-19 mediators like disrupted renin angiotensin system, oxidative stress, cytokine storm, fever, and the mental stress on reproductive physiology have also been discussed. For the present study, various keywords were used to search literature on PubMed, ScienceDirect, and Google Scholar databases. Articles were screened for relevancy and were studied in detail for qualitative synthesis of the review. Through our literature review, we found a multitude of effects of COVID-19 mediators on reproductive systems. Studies reported expression of receptors like ACE-2, TMPRSS2, and CD147 in the testes, epididymis, prostrate, seminal vesicles, and ovarian follicles. These proteins are known to serve as major SARS-CoV-2 entry factors. The expression of lysosomal cathepsins (CTSB/CTSL) and/ neuropilin-1 (NRP-1) are also evident in the testes, epididymis, seminal vesicles, fallopian tube, cervix, and endometrium. The binding of viral spike protein with ACE-2 was found to alter the renin-angiotensin cascade, which could invite additional infertility problems. Furthermore, COVID-19 mediated cytokine storm, oxidative stress, and elevated body temperature could be detrimental to gametogenesis, steroidogenesis, and reproductive cycles in patients. Finally, social isolation, confinement, and job insecurities have fueled mental stress and frustration that might promote glucocorticoid-mediated subnormal sperm quality in men and higher risk of miscarriage in women. Hence, the influence of COVID-19 on the alteration of reproductive health and fertility is quite apparent.
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Affiliation(s)
- Prem Rajak
- Department of Animal Science, Kazi Nazrul University, Asansol, West Bengal, India.
| | - Sumedha Roy
- Department of Biomolecular Medicine, Faculty of Medicine and Health Sciences, Ghent University, Belgium
| | - Moumita Dutta
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, WA, USA
| | - Sayanti Podder
- Post Graduate Department of Zoology, Modern College of Arts, Science and Commerce, Ganeshkhind, Pune, Maharashtra, India
| | - Saurabh Sarkar
- Department of Zoology, Gushkara Mahavidyalaya, Gushkara, Purba Bardhaman, West Bengal, India
| | - Abhratanu Ganguly
- Post Graduate Department of Zoology, A.B.N. Seal College, Cooch Behar, West Bengal, India
| | - Moutushi Mandi
- Toxicology Research Unit, Department of Zoology, The University of Burdwan, Purba Bardhaman, West Bengal, India
| | - Salma Khatun
- Department of Zoology, Krishna Chandra College, Hetampur, West Bengal, India
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27
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Cui Y, Chen F, Gao J, Lei M, Wang D, Jin X, Guo Y, Shan L, Chen X. Comprehensive landscape of the renin-angiotensin system in Pan-cancer: a potential downstream mediated mechanism of SARS-CoV-2. Int J Biol Sci 2021; 17:3795-3817. [PMID: 34671200 PMCID: PMC8495399 DOI: 10.7150/ijbs.53312] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Accepted: 08/06/2021] [Indexed: 11/23/2022] Open
Abstract
Background: SARS-CoV-2, the cause of the worldwide COVID-19 pandemic, utilizes the mechanism of binding to ACE2 (a crucial component of the renin-angiotensin system [RAS]), subsequently mediating a secondary imbalance of the RAS family and leading to severe injury to the host. However, very few studies have been conducted to reveal the mechanism behind the effect of SARS-CoV-2 on tumors. Methods: Demographic data extracted from 33 cancer types and over 10,000 samples were employed to determine the comprehensive landscape of the RAS. Expression distribution, pretranscriptional and posttranscriptional regulation and posttranslational modifications (PTMs) as well as genomic alterations, DNA methylation and m6A modification were analyzed in both tissue and cell lines. The clinical phenotype, prognostic value and significance of the RAS during immune infiltration were identified. Results: Low expression of AGTR1 was common in tumors compared to normal tissues, while very low expression of AGTR2 and MAS1 was detected in both tissues and cell lines. Differential expression patterns of ACE in ovarian serous cystadenocarcinoma (OV) and kidney renal clear cell carcinoma (KIRC) were correlated with ubiquitin modification involving E3 ligases. Genomic alterations of the RAS family were infrequent across TCGA pan-cancer program, and ACE had the highest alteration frequency compared with other members. Low expression of AGTR1 may result from hypermethylation in the promoter. Downregulation of RAS family was linked to higher clinical stage and worse survival (as measured by disease-specific survival [DSS], overall survival [OS] or progression-free interval [PFI]), especially for ACE2 and AGTR1 in KIRC. ACE-AGTR1, a classical axis of the RAS family related to immune infiltration, was positively correlated with M2-type macrophages, cancer-associated fibroblasts (CAFs) and immune checkpoint genes in most cancers. Conclusion: ACE, ACE2, AGT and AGTR1 were differentially expressed in 33 types of cancers. PTM of RAS family was found to rely on ubiquitination. ACE2 and AGTR1 might serve as independent prognostic factors for LGG and KIRC. SARS-CoV-2 might modify the tumor microenvironment by regulating the RAS family, thus affecting the biological processes of cancer.
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Affiliation(s)
- Yuqing Cui
- The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150040, China
| | - Fengzhi Chen
- The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150040, China
| | - Jiayi Gao
- The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150040, China
| | - Mengxia Lei
- The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150040, China
| | - Dandan Wang
- The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150040, China
| | - Xiaoying Jin
- The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150040, China
| | - Yan Guo
- The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150040, China
| | - Liying Shan
- The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150040, China
| | - Xuesong Chen
- The Fourth Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin 150040, China
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Qiao ZW, Jiang Y, Wang L, Wang L, Jiang J, Zhang JR, Mu P. LINC00852 promotes the proliferation and invasion of ovarian cancer cells by competitively binding with miR-140-3p to regulate AGTR1 expression. BMC Cancer 2021; 21:1004. [PMID: 34496800 PMCID: PMC8424870 DOI: 10.1186/s12885-021-08730-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2020] [Accepted: 08/25/2021] [Indexed: 12/29/2022] Open
Abstract
Background Dysregulation of long non-coding RNAs (lncRNAs) has been identified in ovarian cancer. However, the expression and biological functions of LINC00852 in ovarian cancer are not understood. Methods The expressions of LINC00852, miR-140-3p and AGTR1 mRNA in ovarian cancer tissues and cells were detected by quantitative reverse transcription polymerase chain reaction (qRT-PCR) assay. Gain- and loss-of-function assays were performed to explore the biological functions of LINC00852 and miR-140-3p in the progression of ovarian cancer in vitro. The bindings between LINC00852 and miR-140-3p were confirmed by luciferase reporter gene assay, RNA immunoprecipitation (RIP) assay and RNA pull-down assay. Results We found that LINC00852 expression was significantly up-regulated in ovarian cancer tissues and cells, whereas miR-140-3p expression was significantly down-regulated in ovarian cancer tissues. Functionally, LINC00852 knockdown inhibited the viability, proliferation and invasion of ovarian cancer cells, and promoted the apoptosis of ovarian cancer cells. Further investigation showed that LINC00852 interacted with miR-140-3p, and miR-140-3p overexpression suppressed the viability, proliferation and invasion of ovarian cancer cells. In addition, miR-140-3p interacted with AGTR1 and negatively regulated its level in ovarian cancer cells. Mechanistically, we found that LINC00852 acted as a ceRNA of miR-140-3p to promote AGTR1 expression and activate MEK/ERK/STAT3 pathway. Finally, LINC00852 knockdown inhibited the growth and invasion ovarian cancer in vivo. Conclusion LINC00852/miR-140-3p/AGTR1 is an important pathway to promote the proliferation and invasion of ovarian cancer.
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Affiliation(s)
- Zhi-Wei Qiao
- Department of Gynaecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, No.44, Xiaoheyan Road, Shenyang, 110042, Liaoning Province, China
| | - Ying Jiang
- Department of Gynaecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, No.44, Xiaoheyan Road, Shenyang, 110042, Liaoning Province, China
| | - Ling Wang
- Department of Gynaecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, No.44, Xiaoheyan Road, Shenyang, 110042, Liaoning Province, China
| | - Lei Wang
- Department of Gynaecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, No.44, Xiaoheyan Road, Shenyang, 110042, Liaoning Province, China
| | - Jing Jiang
- Department of Gynaecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, No.44, Xiaoheyan Road, Shenyang, 110042, Liaoning Province, China
| | - Jing-Ru Zhang
- Department of Gynaecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, No.44, Xiaoheyan Road, Shenyang, 110042, Liaoning Province, China.
| | - Peng Mu
- Department of Gynaecology, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Insititute, No.44, Xiaoheyan Road, Shenyang, 110042, Liaoning Province, China.
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Liu S, Wu M, Wang F. Research Progress in Prognostic Factors and Biomarkers of Ovarian Cancer. J Cancer 2021; 12:3976-3996. [PMID: 34093804 PMCID: PMC8176232 DOI: 10.7150/jca.47695] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2020] [Accepted: 04/22/2021] [Indexed: 12/14/2022] Open
Abstract
Ovarian cancer is a serious threat to women's health; its early diagnosis rate is low and prone to metastasis and recurrence. The current conventional treatment for ovarian cancer is a combination of platinum and paclitaxel chemotherapy based on surgery. The recurrence and progression of ovarian cancer with poor prognosis is a major challenge in treatment. With rapid advances in technology, understanding of the molecular pathways involved in ovarian cancer recurrence and progression has increased, biomarker-guided treatment options can greatly improve the prognosis of patients. This review systematically discusses and summarizes existing and new information on prognostic factors and biomarkers of ovarian cancer, which is expected to improve the clinical management of patients and lead to effective personalized treatment.
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Affiliation(s)
- Shuna Liu
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China, 210029
- National Key Clinical Department of Laboratory Medicine, Nanjing, China, 210029
| | - Ming Wu
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China, 210029
- National Key Clinical Department of Laboratory Medicine, Nanjing, China, 210029
| | - Fang Wang
- Department of Laboratory Medicine, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China, 210029
- National Key Clinical Department of Laboratory Medicine, Nanjing, China, 210029
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Unraveling the Molecular Nexus between GPCRs, ERS, and EMT. Mediators Inflamm 2021; 2021:6655417. [PMID: 33746610 PMCID: PMC7943314 DOI: 10.1155/2021/6655417] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2020] [Revised: 02/23/2021] [Accepted: 02/25/2021] [Indexed: 12/12/2022] Open
Abstract
G protein-coupled receptors (GPCRs) represent a large family of transmembrane proteins that transduce an external stimulus into a variety of cellular responses. They play a critical role in various pathological conditions in humans, including cancer, by regulating a number of key processes involved in tumor formation and progression. The epithelial-mesenchymal transition (EMT) is a fundamental process in promoting cancer cell invasion and tumor dissemination leading to metastasis, an often intractable state of the disease. Uncontrolled proliferation and persistent metabolism of cancer cells also induce oxidative stress, hypoxia, and depletion of growth factors and nutrients. These disturbances lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER) and induce a cellular condition called ER stress (ERS) which is counteracted by activation of the unfolded protein response (UPR). Many GPCRs modulate ERS and UPR signaling via ERS sensors, IRE1α, PERK, and ATF6, to support cancer cell survival and inhibit cell death. By regulating downstream signaling pathways such as NF-κB, MAPK/ERK, PI3K/AKT, TGF-β, and Wnt/β-catenin, GPCRs also upregulate mesenchymal transcription factors including Snail, ZEB, and Twist superfamilies which regulate cell polarity, cytoskeleton remodeling, migration, and invasion. Likewise, ERS-induced UPR upregulates gene transcription and expression of proteins related to EMT enhancing tumor aggressiveness. Though GPCRs are attractive therapeutic targets in cancer biology, much less is known about their roles in regulating ERS and EMT. Here, we will discuss the interplay in GPCR-ERS linked to the EMT process of cancer cells, with a particular focus on oncogenes and molecular signaling pathways.
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Abstract
Secretory proteins in tumor tissues are important components of the tumor microenvironment. Secretory proteins act on tumor cells or stromal cells or mediate interactions between tumor cells and stromal cells, thereby affecting tumor progression and clinical treatment efficacy. In this paper, recent research advances in secretory proteins in malignant tumors are reviewed.
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Affiliation(s)
- Na Zhang
- State Key Laboratory of Molecular Oncology, Center for Cancer Precision Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Jiajie Hao
- State Key Laboratory of Molecular Oncology, Center for Cancer Precision Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Yan Cai
- State Key Laboratory of Molecular Oncology, Center for Cancer Precision Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
| | - Mingrong Wang
- State Key Laboratory of Molecular Oncology, Center for Cancer Precision Medicine, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
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Chaudhari S, Dey Pereira S, Asare-Warehene M, Naha R, Kabekkodu SP, Tsang BK, Satyamoorthy K. Comorbidities and inflammation associated with ovarian cancer and its influence on SARS-CoV-2 infection. J Ovarian Res 2021; 14:39. [PMID: 33632295 PMCID: PMC7906086 DOI: 10.1186/s13048-021-00787-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/21/2020] [Accepted: 02/09/2021] [Indexed: 12/29/2022] Open
Abstract
Coronavirus disease 2019 (COVID-19) caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) worldwide is a major public health concern. Cancer patients are considered a vulnerable population to SARS-CoV-2 infection and may develop several COVID-19 symptoms. The heightened immunocompromised state, prolonged chronic pro-inflammatory milieu coupled with comorbid conditions are shared in both disease conditions and may influence patient outcome. Although ovarian cancer (OC) and COVID-19 are diseases of entirely different primary organs, both diseases share similar molecular and cellular characteristics in their microenvironment suggesting a potential cooperativity leading to poor outcome. In COVID-19 related cases, hospitalizations and deaths worldwide are lower in women than in males; however, comorbidities associated with OC may increase the COVID-19 risk in women. The women at the age of 50-60 years are at greater risk of developing OC as well as SARS-CoV-2 infection. Increased levels of gonadotropin and androgen, dysregulated renin-angiotensin-aldosterone system (RAAS), hyper-coagulation and chronic inflammation are common conditions observed among OC and severe cases of COVID-19. The upregulation of common inflammatory cytokines and chemokines such as tumor necrosis factor α (TNF-α), interleukin (IL)-1β, IL-2, IL-6, IL-10, interferon-γ-inducible protein 10 (IP-10), granulocyte colony-stimulating factor (G-CSF), monocyte chemoattractant protein-1 (MCP-1), macrophage colony-stimulating factor (M-CSF), among others in the sera of COVID-19 and OC subjects suggests potentially similar mechanism(s) involved in the hyper-inflammatory condition observed in both disease states. Thus, it is conceivable that the pathogenesis of OC may significantly contribute to the potential infection by SARS-CoV-2. Our understanding of the influence and mechanisms of SARS-CoV-2 infection on OC is at an early stage and in this article, we review the underlying pathogenesis presented by various comorbidities of OC and correlate their influence on SARS-CoV-2 infection.
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Affiliation(s)
- Sima Chaudhari
- Department of Cell and Molecular Biology, Manipal School of Life Science, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Satyajit Dey Pereira
- Department of Cell and Molecular Biology, Manipal School of Life Science, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Meshach Asare-Warehene
- Chronic Disease Program, Ottawa Hospital Research Institute and Department of Obstetrics & Gynecology and Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, K1N 6N5, Canada
| | - Ritam Naha
- Department of Cell and Molecular Biology, Manipal School of Life Science, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Shama Prasada Kabekkodu
- Department of Cell and Molecular Biology, Manipal School of Life Science, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India
| | - Benjamin K Tsang
- Chronic Disease Program, Ottawa Hospital Research Institute and Department of Obstetrics & Gynecology and Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, K1N 6N5, Canada
| | - Kapaettu Satyamoorthy
- Department of Cell and Molecular Biology, Manipal School of Life Science, Manipal Academy of Higher Education, Manipal, Karnataka, 576104, India.
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Xu X, Lu Y, Wu Y, Wang M, Wang X, Wang H, Chen B, Li Y. A signature of seven immune-related genes predicts overall survival in male gastric cancer patients. Cancer Cell Int 2021; 21:117. [PMID: 33602220 PMCID: PMC7891008 DOI: 10.1186/s12935-021-01823-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 01/06/2021] [Accepted: 02/09/2021] [Indexed: 12/24/2022] Open
Abstract
Background Gastric cancer (GC) has a high mortality rate and is one of the most fatal malignant tumours. Male sex has been proven as an independent risk factor for GC. This study aimed to identify immune-related genes (IRGs) associated with the prognosis of male GC. Methods RNA sequencing and clinical data were obtained from The Cancer Genome Atlas (TCGA) database. Differentially expressed IRGs between male GC and normal tissues were identified by integrated bioinformatics analysis. Univariate and multivariate Cox regression analyses were applied to screen survival-associated IRGs. Then, GC patients were separated into high- and low-risk groups based on the median risk score. Furthermore, a nomogram was constructed based on the TCGA dataset. The prognostic value of the risk signature model was evaluated by Kaplan-Meier curve, receiver operating characteristic (ROC), Harrell’s concordance index and calibration curves. In addition, the gene expression dataset from the Gene Expression Omnibus (GEO) was also downloaded for external validation. The relative proportions of 22 types of infiltrating immune cells in each male GC sample were evaluated using CIBERSORT. Results
A total of 276 differentially expressed IRGs were screened, including 189 up-regulated and 87 down-regulated genes. Subsequently, a seven-IRGs signature (LCN12, CCL21, RNASE2, CGB5, NRG4, AGTR1 and NPR3) was identified to be significantly associated with the overall survival (OS) of male GC patients. Survival analysis indicated that patients in the high-risk group exhibited a poor clinical outcome. The results of multivariate analysis revealed that the risk score was an independent prognostic factor. The established nomogram could be used to evaluate the prognosis of individual male GC patients. Further analysis showed that the prognostic model had excellent predictive performance in both TCGA and validated cohorts. Besides, the results of tumour-infiltrating immune cell analysis indicated that the seven-IRGs signature could reflect the status of the tumour immune microenvironment. Conclusions Our study developed a novel seven-IRGs risk signature for individualized survival prediction of male GC patients.
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Affiliation(s)
- Xin Xu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 218 JiXi Avenue, Hefei, 230022, Anhui, China.,Anhui Medical University, Hefei, 230022, China
| | - Yida Lu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 218 JiXi Avenue, Hefei, 230022, Anhui, China.,Anhui Medical University, Hefei, 230022, China
| | - Youliang Wu
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 218 JiXi Avenue, Hefei, 230022, Anhui, China.,Anhui Medical University, Hefei, 230022, China
| | - Mingliang Wang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 218 JiXi Avenue, Hefei, 230022, Anhui, China.,Anhui Medical University, Hefei, 230022, China
| | - Xiaodong Wang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 218 JiXi Avenue, Hefei, 230022, Anhui, China.,Anhui Medical University, Hefei, 230022, China
| | - Huizhen Wang
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 218 JiXi Avenue, Hefei, 230022, Anhui, China
| | - Bo Chen
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 218 JiXi Avenue, Hefei, 230022, Anhui, China
| | - Yongxiang Li
- Department of General Surgery, The First Affiliated Hospital of Anhui Medical University, 218 JiXi Avenue, Hefei, 230022, Anhui, China.
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Ziaja M, Urbanek KA, Kowalska K, Piastowska-Ciesielska AW. Angiotensin II and Angiotensin Receptors 1 and 2-Multifunctional System in Cells Biology, What Do We Know? Cells 2021; 10:cells10020381. [PMID: 33673178 PMCID: PMC7917773 DOI: 10.3390/cells10020381] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2021] [Revised: 02/05/2021] [Accepted: 02/09/2021] [Indexed: 12/13/2022] Open
Abstract
For years, the renin-angiotensin system (RAS) has been perceived as a system whose role is to primarily modulate the functioning of the cardiovascular system. Years of research into the role of RAS have provided the necessary data to confirm that the role of RAS is very complex and not limited to the cardiovascular system. The presence of individual elements of the renin-angiotensin (RA) system allows to control many processes, ranging from the memorization to pro-cancer processes. Maintaining the proportions between the individual axes of the RA system allows for achieving a balance, often called homeostasis. Thus, any disturbance in the expression or activity of individual RAS elements leads to pathophysiological processes.
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Sun N, Gao P, Li Y, Yan Z, Peng Z, Zhang Y, Han F, Qi X. Screening and Identification of Key Common and Specific Genes and Their Prognostic Roles in Different Molecular Subtypes of Breast Cancer. Front Mol Biosci 2021; 8:619110. [PMID: 33644115 PMCID: PMC7905399 DOI: 10.3389/fmolb.2021.619110] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2020] [Accepted: 01/08/2021] [Indexed: 01/27/2023] Open
Abstract
Breast cancer is one of the most common cancers. Although the present molecular classification improves the treatment effect and prognosis of breast cancer, the heterogeneity of the molecular subtype remains very complex, and the applicability and effectiveness of treatment methods are still limited leading to poorer patient prognosis than expected. Further identification of more refined molecular typing based on gene expression profile will yield better understanding of the heterogeneity, improving treatment effects and prolonging prognosis of patients. Here, we downloaded the mRNA expression profiles and corresponding clinical data of patients with breast cancer from public databases and performed typical molecular typing using PAM50 (Prediction Analysis of Microarray 50) method. Comparative analyses were performed to screen the common and specific differentially expressed genes (DEGs) between cancer and corresponding para-cancerous tissues in each breast cancer subtype. The GO and KEGG analyses of the DEGs were performed to enrich the common and specific functional progress and signaling pathway involved in breast cancer subtypes. A total of 38 key common and specific DEGs were identified and selected based on the validated results, GO/KEGG enrichments, and the priority of expression, including four common DEGs and 34 specific DEGs in different subtypes. The prognostic value of these key common and specific DEGs was further analyzed to obtain useful potential markers in clinic. Finally, the potential roles and the specific prognostic values of the common and specific DEGs were speculated and summarized in total breast cancer and different subtype breast cancer based on the results of these analyses. The findings of our study provide the basis of more refined molecular typing of breast cancer, potential new therapeutic targets and prognostic markers for different breast cancer subtypes
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Affiliation(s)
- Na Sun
- Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Chongqing, China
| | - Pingping Gao
- Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Chongqing, China
| | - Yanling Li
- Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Chongqing, China
| | - Zexuan Yan
- Institute of Pathology and Southwest Cancer Center, Key Laboratory of the Ministry of Education, Southwest Hospital, Army Medical University, Chongqing, China
| | - Zaihui Peng
- Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Chongqing, China
| | - Yi Zhang
- Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Chongqing, China
| | - Fei Han
- Institute of Toxicology, College of Preventive Medicine, Army Medical University, Chongqing, China
| | - Xiaowei Qi
- Department of Breast and Thyroid Surgery, Southwest Hospital, Army Medical University, Chongqing, China
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Lee HY, Son SW, Moeng S, Choi SY, Park JK. The Role of Noncoding RNAs in the Regulation of Anoikis and Anchorage-Independent Growth in Cancer. Int J Mol Sci 2021; 22:ijms22020627. [PMID: 33435156 PMCID: PMC7827914 DOI: 10.3390/ijms22020627] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2020] [Revised: 01/02/2021] [Accepted: 01/06/2021] [Indexed: 12/11/2022] Open
Abstract
Cancer is a global health concern, and the prognosis of patients with cancer is associated with metastasis. Multistep processes are involved in cancer metastasis. Accumulating evidence has shown that cancer cells acquire the capacity of anoikis resistance and anchorage-independent cell growth, which are critical prerequisite features of metastatic cancer cells. Multiple cellular factors and events, such as apoptosis, survival factors, cell cycle, EMT, stemness, autophagy, and integrins influence the anoikis resistance and anchorage-independent cell growth in cancer. Noncoding RNAs (ncRNAs), such as microRNAs (miRNAs) and long noncoding RNAs (lncRNAs), are dysregulated in cancer. They regulate cellular signaling pathways and events, eventually contributing to cancer aggressiveness. This review presents the role of miRNAs and lncRNAs in modulating anoikis resistance and anchorage-independent cell growth. We also discuss the feasibility of ncRNA-based therapy and the natural features of ncRNAs that need to be contemplated for more beneficial therapeutic strategies against cancer.
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Almutlaq M, Alamro AA, Alamri HS, Alghamdi AA, Barhoumi T. The Effect of Local Renin Angiotensin System in the Common Types of Cancer. Front Endocrinol (Lausanne) 2021; 12:736361. [PMID: 34539580 PMCID: PMC8446618 DOI: 10.3389/fendo.2021.736361] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2021] [Accepted: 08/13/2021] [Indexed: 12/12/2022] Open
Abstract
The Renin Angiotensin System (RAS) is a hormonal system that is responsible for blood pressure hemostasis and electrolyte balance. It is implicated in cancer hallmarks because it is expressed locally in almost all of the body's tissues. In this review, current knowledge on the effect of local RAS in the common types of cancer such as breast, lung, liver, prostate and skin cancer is summarised. The mechanisms by which RAS components could increase or decrease cancer activity are also discussed. In addition to the former, this review explores how the administration of AT1R blockers and ACE inhibitors drugs intervene with cancer therapy and contribute to the outcomes of cancer.
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Affiliation(s)
- Moudhi Almutlaq
- King Abdullah International Medical Research Centre, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
- Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia
- *Correspondence: Moudhi Almutlaq, ; Tlili Barhoumi,
| | - Abir Abdullah Alamro
- Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Hassan S. Alamri
- King Abdullah International Medical Research Centre, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
- Medical Research Core Facility and Platforms, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
| | - Amani Ahmed Alghamdi
- Biochemistry Department, College of Science, King Saud University, Riyadh, Saudi Arabia
| | - Tlili Barhoumi
- King Abdullah International Medical Research Centre, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
- Medical Research Core Facility and Platforms, King Saud bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia
- *Correspondence: Moudhi Almutlaq, ; Tlili Barhoumi,
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Singh A, Srivastava N, Yadav A, Ateeq B. Targeting AGTR1/NF-κB/CXCR4 axis by miR-155 attenuates oncogenesis in glioblastoma. Neoplasia 2020; 22:497-510. [PMID: 32896760 PMCID: PMC7481885 DOI: 10.1016/j.neo.2020.08.002] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 08/01/2020] [Accepted: 08/05/2020] [Indexed: 01/05/2023]
Abstract
Glioblastoma (GBM) represents the most aggressive malignancy of the central nervous system. Increased expression of Angiotensin II Receptor Type 1 (AGTR1) has been associated with proliferative and infiltrative properties of glioma cells. However, the underlying mechanism of AGTR1 upregulation in GBM is still unexplored. To understand the post-transcriptional regulation of AGTR1 in GBM, we screened 3'untranslated region (3'UTR) of AGTR1 for putative miRNA binding by using prediction algorithms. Interestingly, miR-155 showed conserved binding on the 3'UTR of AGTR1, subsequently confirmed by luciferase reporter assay. Furthermore, miR-155 overexpressing GBM cells show decrease in AGTR1 expression accompanied with reduced cell proliferation, invasion, foci formation and anchorage-independent growth. Strikingly, immunodeficient mice implanted with stable miR-155 overexpressing SNB19 cells show negligible tumor growth. Notably, miR-155 attenuates NF-κB signaling downstream of AGTR1 leading to reduced CXCR4 as well as AGTR1 levels. Mechanistically, miR-155 mitigates AGTR1-mediated angiogenesis, epithelial-to-mesenchymal transition, stemness, and MAPK signaling. Similar effects were observed by using pharmacological inhibitor of IκB Kinase (IKK) complex in multiple cell-based assays. Taken together, we established that miRNA-155 post-transcriptionally regulates AGTR1 expression, abrogates AGTR1/NF-κB/CXCR4 signaling axis and elicits pleiotropic anticancer effects in GBM. This study opens new avenues for using IKK inhibitors and miRNA-155 replacement therapies for the treatment of AGTR1-positive malignancies.
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MESH Headings
- Animals
- Apoptosis
- Brain Neoplasms/genetics
- Brain Neoplasms/metabolism
- Brain Neoplasms/pathology
- Cell Movement
- Cell Proliferation
- Female
- Gene Expression Regulation, Neoplastic
- Glioblastoma/genetics
- Glioblastoma/metabolism
- Glioblastoma/pathology
- Humans
- Mice
- Mice, Inbred NOD
- Mice, SCID
- MicroRNAs/genetics
- NF-kappa B/genetics
- NF-kappa B/metabolism
- Receptor, Angiotensin, Type 1/genetics
- Receptor, Angiotensin, Type 1/metabolism
- Receptors, CXCR4/genetics
- Receptors, CXCR4/metabolism
- Tumor Cells, Cultured
- Xenograft Model Antitumor Assays
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Affiliation(s)
- Anukriti Singh
- Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208016, U.P., India; Department of Bioscience and Biotechnology, Banasthali Vidyapith, Banasthali 304022, Rajasthan, India
| | - Nidhi Srivastava
- Department of Bioscience and Biotechnology, Banasthali Vidyapith, Banasthali 304022, Rajasthan, India
| | - Anjali Yadav
- Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208016, U.P., India
| | - Bushra Ateeq
- Molecular Oncology Laboratory, Department of Biological Sciences and Bioengineering, Indian Institute of Technology Kanpur, Kanpur 208016, U.P., India; Mehta Family Center for Engineering in Medicine, Indian Institute of Technology Kanpur, Kanpur 208016, U.P., India.
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Lipids in the tumor microenvironment: From cancer progression to treatment. Prog Lipid Res 2020; 80:101055. [PMID: 32791170 DOI: 10.1016/j.plipres.2020.101055] [Citation(s) in RCA: 240] [Impact Index Per Article: 48.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 08/05/2020] [Accepted: 08/07/2020] [Indexed: 12/11/2022]
Abstract
Over the past decade, the study of metabolic abnormalities in cancer cells has risen dramatically. Cancer cells can thrive in challenging environments, be it the hypoxic and nutrient-deplete tumor microenvironment or a distant tissue following metastasis. The ways in which cancer cells utilize lipids are often influenced by the complex interactions within the tumor microenvironment and adjacent stroma. Adipocytes can be activated by cancer cells to lipolyze their triglyceride stores, delivering secreted fatty acids to cancer cells for uptake through numerous fatty acid transporters. Cancer-associated fibroblasts are also implicated in lipid secretion for cancer cell catabolism and lipid signaling leading to activation of mitogenic and migratory pathways. As these cancer-stromal interactions are exacerbated during tumor progression, fatty acids secreted into the microenvironment can impact infiltrating immune cell function and phenotype. Lipid metabolic abnormalities such as increased fatty acid oxidation and de novo lipid synthesis can provide survival advantages for the tumor to resist chemotherapeutic and radiation treatments and alleviate cellular stresses involved in the metastatic cascade. In this review, we highlight recent literature that demonstrates how lipids can shape each part of the cancer lifecycle and show that there is significant potential for therapeutic intervention surrounding lipid metabolic and signaling pathways.
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Lysophosphatidic acid modulates ovarian cancer multicellular aggregate assembly and metastatic dissemination. Sci Rep 2020; 10:10877. [PMID: 32616784 PMCID: PMC7331713 DOI: 10.1038/s41598-020-67565-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2020] [Accepted: 06/10/2020] [Indexed: 12/13/2022] Open
Abstract
Epithelial ovarian cancer (EOC) metastasis occurs by exfoliation of cells and multicellular aggregates (MCAs) from the tumor into the peritoneal cavity, adhesion to and retraction of peritoneal mesothelial cells and subsequent anchoring. Elevated levels of lysophosphatidic acid (LPA) have been linked to aberrant cell proliferation, oncogenesis, and metastasis. LPA disrupts junctional integrity and epithelial cohesion in vitro however, the fate of free-floating cells/MCAs and the response of host peritoneal tissues to LPA remain unclear. EOC MCAs displayed significant LPA-induced changes in surface ultrastructure with the loss of cell surface protrusions and poor aggregation, resulting in increased dissemination of small clusters compared to untreated control MCAs. LPA also diminished the adhesive capacity of EOC single cells and MCAs to murine peritoneal explants and impaired MCA survival and mesothelial clearance competence. Peritoneal tissues from healthy mice injected with LPA exhibited enhanced mesothelial surface microvilli. Ultrastructural alterations were associated with restricted peritoneal susceptibility to metastatic colonization by single cells as well as epithelial-type MCAs. The functional consequence is an LPA-induced dissemination of small mesenchymal-type clusters, promoting a miliary mode of peritoneal seeding that complicates surgical removal and is associated with worse prognosis.
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Involvement of ACE2/Ang-(1-7)/MAS1 Axis in the Regulation of Ovarian Function in Mammals. Int J Mol Sci 2020; 21:ijms21134572. [PMID: 32604999 PMCID: PMC7369927 DOI: 10.3390/ijms21134572] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 06/20/2020] [Accepted: 06/22/2020] [Indexed: 12/14/2022] Open
Abstract
In addition to the classic, endocrine renin-angiotensin system, local renin-angiotensin system (RAS) has been documented in many tissues and organs, including the ovaries. The localization and functional activity of the two opposing axes of the system, viz. ACE1/Ang II/AT1 and ACE2/Ang-(1-7)/MAS1, differs between animal species and varied according to the stage of follicle development. It appears that the angiotensin peptides and their receptors participate in reproductive processes such as folliculogenesis, steroidogenesis, oocyte maturation, and ovulation. In addition, changes in the constituent compounds of local RAS may contribute to pathological conditions, such as polycystic ovary syndrome, ovarian hyperstimulation syndrome, and ovarian cancer. This review article examines the expression, localization, metabolism, and activity of individual elements of the ACE2/Ang-(1-7)/MAS1 axis in the ovaries of various animal species. The manuscript also presents the relationship between the secretion of gonadotropins and sex hormones and expression of Ang-(1-7) and MAS1 receptors. It also summarizes current knowledge regarding the positive and negative impact of ACE2/Ang-(1-7)/MAS1 axis on ovarian function.
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Evaluating the benefits of renin-angiotensin system inhibitors as cancer treatments. Pharmacol Ther 2020; 211:107527. [PMID: 32173557 DOI: 10.1016/j.pharmthera.2020.107527] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 03/08/2020] [Indexed: 02/07/2023]
Abstract
G-protein-coupled receptors (GPCRs) are the largest and most diverse group of cellular membrane receptors identified and characterized. It is estimated that 30 to 50% of marketed drugs target these receptors. The angiotensin II receptor type 1 (AT1R) is a GPCR which signals in response to systemic alterations of the peptide hormone angiotensin II (AngII) in circulation. The enzyme responsible for converting AngI to AngII is the angiotensin-converting enzyme (ACE). Specific inhibitors for the AT1R (more commonly known as AT1R blockers or antagonists) and ACE are well characterized for their effects on the cardiovascular system. Combined with the extensive clinical data available on patient tolerance of AT1R blockers (ARBs) and ACE inhibitors (ACEIs), as well as their non-classical roles in cancer, the notion of repurposing this class of medications as cancer treatment(s) is explored in the current review. Given that AngII-dependent AT1R activity directly regulates angiogenesis, remodeling of vasculature, pro-inflammatory responses, stem cell programming and hematopoiesis, and electrolyte balance; the modulation of these processes with pharmacologically well characterized medications could present a valuable complementary treatment option for cancer patients.
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Ashrafizadeh M, Mohammadinejad R, Samarghandian S, Yaribeygi H, Johnston TP, Sahebkar A. Anti-Tumor Effects of Osthole on Different Malignant Tissues: A Review of Molecular Mechanisms. Anticancer Agents Med Chem 2020; 20:918-931. [PMID: 32108003 DOI: 10.2174/1871520620666200228110704] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2019] [Revised: 12/09/2019] [Accepted: 01/29/2020] [Indexed: 12/16/2022]
Abstract
Cancer management and/or treatment require a comprehensive understanding of the molecular and signaling pathways involved. Recently, much attention has been directed to these molecular and signaling pathways, and it has been suggested that a number of biomolecules/players involved in such pathways, such as PI3K/Akt, NF-kB, STAT, and Nrf2 contribute to the progression, invasion, proliferation, and metastasis of malignant cells. Synthetic anti-tumor agents and chemotherapeutic drugs have been a mainstay in cancer therapy and are widely used to suppress the progression and, hopefully, halt the proliferation of malignant cells. However, these agents have some undesirable side-effects and, therefore, naturally-occurring compounds with high potency and fewer side-effects are now of great interest. Osthole is a plant-derived chemical compound that can inhibit the proliferation of malignant cells and provide potent anti-cancer effects in various tissues. Therefore, in this review, we presented the main findings concerning the potential anti-tumor effects of osthole and its derivatives and described possible molecular mechanisms by which osthole may suppress malignant cell proliferation in different tissues.
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Affiliation(s)
- Milad Ashrafizadeh
- Department of Basic Science, Faculty of Veterinary Medicine, University of Tabriz, Tabriz, Iran
| | - Reza Mohammadinejad
- Pharmaceutics Research Center, Institute of Neuropharmacology, Kerman University of Medical Sciences, Kerman, Iran
| | - Saeed Samarghandian
- Department of Basic Medical Sciences, Neyshabur University of Medical Sciences, Neyshabur, Iran
| | - Habib Yaribeygi
- Research Center of Physiology, Semnan University of Medical Sciences, Semnan, Iran
| | - Thomas P Johnston
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO, United States
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