NHC Key Laboratory of Hormones and Development, Tianjin Key Laboratory of Metabolic Diseases, Tianjin Medical University Chu Hsien-I Memorial Hospital & Tianjin Institute of Endocrinology, Tianjin 300134, China.
School of Ophthalmology & Optometry, School of Biomedical Engineering, Wenzhou Medical University, Wenzhou 325035, China.
Acta Biochim Biophys Sin (Shanghai). 2021 Mar 2;53(3):354-364. doi: 10.1093/abbs/gmab002.
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. 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/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 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.
脂质代谢重编程现在被认为是癌症的一个新标志。因此，靶向脂肪生成途径可能是癌症治疗的一个潜在途径。丙戊酸（VPA）作为一种有前途的癌症治疗药物出现；然而，其潜在机制尚未完全理解。在这项研究中，我们旨在研究 VPA 对人前列腺癌细胞 PC-3 和 LNCaP 细胞活力、脂肪生成和细胞凋亡的影响和机制。结果表明，VPA 显著减少脂质积累并诱导 PC-3 和 LNCaP 细胞凋亡。此外，VPA 处理后，PC-3 和 LNCaP 细胞中 CCAAT/增强子结合蛋白α（C/EBPα）以及固醇调节元件结合蛋白 1（SREBP-1）及其下游效应物，包括脂肪酸合酶（FASN）、乙酰辅酶 A 羧化酶 1（ACC1）和抗凋亡 B 细胞淋巴瘤 2（Bcl-2）的表达明显降低。在机制上，C/EBPα 的过表达挽救了 SREBP-1、FASN、ACC1 和 Bcl-2 的水平，增强了脂质积累，并减弱了 VPA 处理的 PC-3 细胞的凋亡。相反，siRNA 敲低 C/EBPα 进一步减少了脂质积累，增强了细胞凋亡，并降低了 SREBP-1、FASN、ACC1 和 Bcl-2 的水平。此外，SREBP-1a 和 1c 增强了 FASN 和 ACC1 的表达，但只有 SREBP-1a 对 VPA 处理的 PC-3 细胞中 Bcl-2 的表达有显著影响。基于这些结果，我们得出结论，VPA 通过降低脂肪生成和通过 C/EBPα/SREBP-1 途径诱导细胞凋亡，显著抑制前列腺癌细胞的活力。因此，靶向脂质代谢和细胞凋亡的 VPA 是 PCa 化疗的一个有前途的候选药物。
