Abstract
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.
Highlights
New effective drugs for prostate cancer (PCa) treatment are urgently needed
We found that the cholesterol esterification inhibitor avasimibe can suppress tumour proliferation and metastasis in vitro and in vivo accompanied by upregulation of E2F-1 protein expression
Avasimibe reduced proliferation in the PCa cells To determine the biological function of Sterol O-acyltransferase1 (SOAT1) in PCa progression, we performed Gene set enrichment analysis (GSEA) using 499 PCa samples
Summary
New effective drugs for prostate cancer (PCa) treatment are urgently needed. Avasimibe was recently identified as a promising drug for anticancer therapies. Prostate cancer (PCa), a common urinary malignancy, is the second most common cause of male morbidity and the fifth most common cause of male mortality worldwide [1]. PCa occupies the first place of morbidity, and its mortality rate ranks 2nd among malignant tumours of males in the United States [2]. PCa mostly occurs in the peripheral zone, without obvious symptoms in the early stage, and metastatic disease is the leading cause of death in prostate cancer patients [3]. Androgen deprivation therapies and castration therapy are the usual methods for the treatment of early PCa [5]. More efficacious and less toxic drugs to treat PCa are needed
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