Withania somnifera root extract inhibits fatty acid synthesis in prostate cancer cells

Su-Hyeong Kim; Krishna B Singh; Eun-Ryeong Hahm; Balakrishna L Lokeshwar; Shivendra V Singh

doi:10.1016/j.jtcme.2020.02.002

Withania somnifera root extract inhibits fatty acid synthesis in prostate cancer cells

J Tradit Complement Med. 2020 Feb 7;10(3):188-197. doi: 10.1016/j.jtcme.2020.02.002. eCollection 2020 May.

Authors

Su-Hyeong Kim¹, Krishna B Singh¹, Eun-Ryeong Hahm¹, Balakrishna L Lokeshwar², Shivendra V Singh^{1

3}

Affiliations

¹ Department of Pharmacology & Chemical Biology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
² Georgia Cancer Center and Department of Medicine, Augusta University, Augusta, GA, USA.
³ UPMC Hillman Cancer Center, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.

Abstract

Prior research argues for a role of increased de novo fatty acid synthesis in pathogenesis of prostate adenocarcinoma, which remains a leading cause of cancer-associated mortality in American men. A safe and effective inhibitor of fatty acid synthesis is still a clinically unmet need. Herein, we investigated the effect of ethanol extract of Withania somnifera root (WRE) standardized for one of its components (withaferin A) on fatty acid synthesis using LNCaP and 22Rv1 human prostate cancer cells. Withania somnifera is a medicinal plant used in the Ayurvedic medicine practiced in India. Western blotting and confocal microscopy revealed a statistically significant decrease in protein levels of key fatty acid metabolism enzymes including ATP citrate lyase (ACLY), acetyl-CoA carboxylase 1 (ACC1), fatty acid synthase (FASN), and carnitine palmitoyltransferase 1A (CPT1A) in WRE-treated cells compared with solvent control. The mRNA levels of ACLY, ACC1, FASN, and CPT1A were also lower in WRE-treated cells in comparison with control. Consequently, WRE treatment resulted in a significant decrease in intracellular levels of acetyl-CoA, total free fatty acids, and neutral lipid droplets in both LNCaP and 22Rv1 cells. WRE exhibited greater potency for fatty acid synthesis inhibition at equimolar concentration than cerulenin and etomoxir. Exposure to WRE results in downregulation of c-Myc and p-Akt(S473) proteins in 22Rv1 cell line. However, overexpression of only c-Myc conferred protection against clonogenic cell survival and lipogenesis inhibition by WRE. In conclusion, these results indicate that WRE is a novel inhibitor of fatty acid synthesis in human prostate cancer cells.

Keywords: ACC1, acetyl-CoA carboxylase 1; ACLY, ATP citrate lyase; ANOVA, one-way analysis of variance; ATP citrate lyase; Acetyl-CoA carboxylase 1; CPT1A, carnitine palmitoyltransferase 1A; CTCF, corrected total cell fluorescence; Cer, cerulenin; Chemoprevention; Eto, etomoxir; FASN, fatty acid synthase; Fatty acid synthase; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; Prostate cancer; Vec, pcDNA3 empty vector transfected cells; WRE, Withania somnifera root extract; caAkt, constitutively active Akt; qRT-PCR, quantitative reverse transcription-polymerase chain reaction.

Abstract

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