Inhibition of lipogenesis and induction of apoptosis by valproic acid in prostate cancer cells via the C/EBPα/SREBP-1 pathway

摘要

Lipid metabolism reprogramming is now accepted as a new hallmark of cancer.Hence,target-ing the lipogenesis pathway may be a potential avenue for cancer treatment.Valproic acid(VPA)emerges as a promising drug for cancer therapy;however,the underlying mechanisms are not yet fully understood.In this study,we aimed to investigate the effects and mechanisms of VPA on cell viability,lipogenesis,and apoptosis in human prostate cancer PC-3 and LNCaP cells.The results showed that VPA significantly reduced lipid accumulation and induced apoptosis of PC-3 and LNCaP cells.Moreover,the expression of CCAAT/enhancer-binding protein α(C/EBPα),as well as sterol regulatory element-binding protein 1(SREBP-1)and its downstream effectors,including fatty acid synthase(FASN),acetyl CoA carboxylase 1(ACC1),and anti-apoptotic B-cell lymphoma 2(Bcl-2),was markedly decreased in PC-3 and LNCaP cells after VPA administration.Mechanistically,the overexpression of C/EBPct rescued the levels of SREBP-1,FASN,ACC1,and Bcl-2,enhanced lipid accumulation,and attenuated apoptosis of VPA-treated PC-3 cells.Conversely,knockdown of C/EBPα by siRNA further decreased lipid accumulation,enhanced apoptosis,and reduced the lev-els of SREBP-1,FASN,ACC1,and Bcl-2.In addition,SREBP-1a and 1c enhanced the expressions of FASN and ACC1,but only SREBP-1a had a significant effect on Bcl-2 expression in VPA-treated PC-3 cells.Based on the results,we concluded that VPA significantly inhibits cell viability via decreasing lipogenesis and inducing apoptosis via the C/EBPα/SREBP-1 pathway in prostate cancer cells.Therefore,VPA that targets lipid metabolism and apoptosis is a promising candidate for PCa chemotherapy.