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

Abstract

Background: Lipid metabolism reprogramming is now accepted as a new hallmark of cancer. Hence, targeting 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. This study aimed to investigate the effects and mechanisms of VPA on cell viability, lipogenesis, and apoptosis in human prostate cancer PC-3 cells. Methods: The effects of VPA on the viability and migration of PC-3 cells were investigated using MTT cell viability assay and wound-healing assay. Oil-Red O staining was used to examine lipid droplets, and DAPI staining assay and Annexin V-FITC and PI double-staining assay were used to measure the extent of cell apoptosis. Quantitative real-time PCR and Western blotting were used to determine the expression of lipogenesis and apoptosis genes. Statistical and analytical data were analyzed with SPSS 17.0 Software, and statistical significance was set to * P < 0.05, ** P < 0.01, and *** P < 0.001 levels. Results: The results showed that VPA significantly reduced lipid accumulation and induced apoptosis of PC-3 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 antiapoptotic B cell lymphoma 2 (Bcl-2), markedly decreased in PC-3 cells after VPA administration. Mechanistically, the overexpression of C/EBPα 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 levels of SREBP-1, FASN, ACC1, and Bcl-2. In addition, SREBP-1a and 1c enhanced the expression of FASN and ACC1, but only SREBP-1a had a significant effect on Bcl-2 expression in VPA-treated PC-3 cells.Conclusions: On the whole, it is concluded that VPA significantly inhibits cell viability via decreasing lipogenesis and inducing apoptosis via the C/EBPα/SREBP-1 pathway in PC-3 cells. Therefore VPA which targets lipid metabolism and apoptosis is a promising candidate for prostate cancer chemotherapy.

Dysregulation of the miRNome unveils a crosstalk between obesity and prostate cancer: miR-107 asa personalized diagnostic and therapeutic tool

“…Notably, these alterations could explain, at least in part, the differential functional in vitro results previously discussed in DU145 versus LNCaP cells, as FASN is a well-known oncogenic driver. 37,38 Interestingly, the alteration in the expression of FASN (at mRNA and protein levels) observed in both prostate cancer cell models in response to the overexpression of miR-107 was not found in the normal-like prostate cell model (PNT2). These results might suggest that the association of miR-107 with the cellular lipid metabolic process could be specific of prostate cancer cells that reinforce the idea that this metabolic cellular process could be one of the main energy pathways used by prostate tumor cells to enhance their aggressiveness features.…”