Withaferin A Inhibits Fatty Acid Synthesis in Rat Mammary Tumors

Withaferin A (WA), which is a small molecule derived from a medicinal plant (Withania somnifera), inhibits growth of human breast cancer xenografts and mammary tumor development in rodent models without any toxicity. However, the mechanism underlying inhibition of mammary cancer development by WA administration is not fully understood. Herein, we demonstrate that the fatty acid synthesis pathway is a novel target of WA in mammary tumors. Treatment of MCF-7 and MDA-MB-231 cells with WA resulted in suppression of fatty acid metabolizing enzymes, including ATP-citrate lyase (ACLY), acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FASN), and carnitine palmitoyltransferase 1A (CPT1A). Expression of FASN and CPT1A was significantly higher in N-methyl-N-nitrosourea-induced mammary tumors in rats when compared with normal mammary tissues. WA-mediated inhibition of mammary tumor development in rats was associated with a statistically significant decrease in expression of ACC1 and FASN and suppression of plasma and/or mammary tumor levels of total free fatty acids and phospholipids. WA administration also resulted in a significant increase in percentage of natural killer cells in the spleen. The protein level of sterol regulatory element binding protein 1 (SREBP1) was decreased in MDA-MB-231 cells after WA treatment. Overexpression of SREBP1 in MDA-MB-231 cells conferred partial but significant protection against WA-mediated downregulation of ACLY and ACC1. In conclusion, circulating and/or mammary tumor levels of fatty acid synthesis enzymes and total free fatty acids may serve as biomarkers of WA efficacy in future clinical trials. PREVENTION RELEVANCE: The present study shows that breast cancer prevention by WA in rats is associated with suppression of fatty acid synthesis.