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

Abstract

Background New 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. Methods In 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. Results The 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. Conclusions Our 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.

Hypercholesterolemia-induced impairment in sorafenib functionality is overcome by avasimibe co-treatment

“…either alone [54][55] or in combination with BCL-ABL-2 inhibitor imatinib [56]. To the best of our knowledge, this is the first study that demonstrates the synergistic cytotoxic effect of SORA and AVA combination on HCC in the presence of LDLc.…”

“…The efficacy was nullified in the presence of high LDLc levels. Recently, the anticancer property of AVA has also been explored either alone [54–55] or in combination with BCL-ABL-2 inhibitor imatinib [56]. To the best of our knowledge, this is the first study that demonstrates the synergistic cytotoxic effect of SORA and AVA combination on HCC in the presence of LDLc.…”

Increased Cholesterol Synthesis Drives Neurotoxicity in Patient Stem Cell-Derived Model of Multiple Sclerosis

“…We identified a secreted signature transcriptionally co-regulated by cholesterol-dependent TFs. The activity of several of the top identified TFs that regulate the aberrant SASP of PMS iNSCs is known to be metabolically modulated by processes targeted by SV treatment in PMS iNSCs: the cholesterol metabolite itself 46-48 , the metabolic pathways of cholesterol synthesis 49 , cholesterol esterification 50 , and FA saturation. 51 While statin-mediated modulation of senescent gene expression has been previously described 53 , SV treatment only induced a minor increase in CDKN2A expression.…”

Repurposing Avasimibe to Inhibit Bacterial Glycosyltransferases

“…Avasimibe has a well-documented solubility and safety profile [ 13 ], although it caused a potential reduction in the potency of Lipitor [ 11 ] and was thus not ultimately used to treat hyperlipidemia or atherosclerosis. Avasimibe also suppresses tumor proliferation and metastasis via the E2F-1 signaling pathway and has potential utility in treating prostate cancer [ 14 ]. Avasimibe alleviates insulin resistance in diet-induced obese mice [ 15 ].…”