The cholesterol esterification inhibitor avasimibe suppresses tumour proliferation and metastasis via the E2F-1 signalling pathway in prostate cancer

Cancer Cell International

Lingao Ju¹  Gang Wang¹  Yu Xiao¹  Kaiyu Qian²  Kangping Xiong³  Siming Chen³  Wei Liu³  Fenfang Zhou³  Tianchen Peng³  Xinghuan Wang⁴ 

[1] Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China;Human Genetic Resource Preservation Center of Hubei Province, Wuhan, China;Human Genetic Resource Preservation Center of Wuhan University, Wuhan, China;Laboratory of Precision Medicine, Zhongnan Hospital of Wuhan University, Wuhan, China;Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China;Department of Biological Repositories, Zhongnan Hospital of Wuhan University, Wuhan, China;Human Genetic Resource Preservation Center of Hubei Province, Wuhan, China;Human Genetic Resource Preservation Center of Wuhan University, Wuhan, China;Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China;Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China;Department of Urology, Zhongnan Hospital of Wuhan University, Wuhan, China;Wuhan Research Center for Infectious Diseases and Cancer, Chinese Academy of Medical Sciences, Wuhan, China;Medical Research Institute, Wuhan University, Wuhan, China;

关键词: Prostate cancer;    Avasimibe;    E2F-1;    Cell cycle;    Metastasis;   

DOI  :  10.1186/s12935-021-02175-5

来源: Springer

【 摘 要 】

BackgroundNew effective drugs for prostate cancer (PCa) treatment are urgently needed. Avasimibe was recently identified as a promising drug for anticancer therapies. The main purpose of this study was to explore the effects and the underlying mechanisms of avasimibe in prostate cancer.MethodsIn this study, MTT and clonogenic survival assays were performed to detect cell proliferation after avasimibe treatment. The effect of avasimibe on cell migration was measured by wound healing and transwell migration assays. Cell cycle distribution and apoptosis were detected by flow cytometry. Immunofluorescence staining and western blot analysis were used to detect the expression of cell cycle-related proteins and epithelial-mesenchymal transition (EMT)-related proteins. In vivo, the antitumour effects of avasimibe were evaluated using a xenograft model and pulmonary metastasis model.ResultsThe study found that avasimibe suppresses tumour growth and triggers G1 phase arrest. Moreover, the expression of the cell cycle-related proteins CDK2/4/6, Cyclin D1 and Cyclin A1 + A2 was significantly increased and p21 expression was decreased after avasimibe treatment. The migration of PCa cells was attenuated after treatment with avasimibe, followed by the downregulation of the expression of the EMT-related proteins N-cadherin, β-catenin, vimentin, Snail and MMP9 and upregulation of E-cadherin expression. Moreover, E2F-1 was elevated after treatment with avasimibe. After knockdown of E2F-1 expression, the inhibition of cell proliferation and migration caused by avasimibe was significantly recovered. The results of the xenograft model showed that avasimibe suppressed tumour growth in vivo. Immunofluorescence staining revealed lower levels of Ki67 and higher levels of E2F-1 in tumour tissues of the avasimibe group than those of the control group. A pulmonary metastasis model also confirmed the inhibition of PCa metastasis by avasimibe. The number of lung metastatic foci in the avasimibe group was significantly decreased compared with that in the control group.ConclusionsOur results suggest that avasimibe can suppress tumour proliferation and metastasis via the E2F-1 signalling pathway. These findings demonstrate the potential of avasimibe as a new effective drug for PCa treatment.

【 授权许可】

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