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Withania somnifera root extract inhibits fatty acid synthesis in prostate cancer cells
Su-Hyeong Kim1, Krishna B Singh1, Eun-Ryeong Hahm1
1Department of Pharmacology & Chemical Biology, 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.
Insights
Ethanol extract of Withania somnifera root (WRE) inhibits fatty acid synthesis in prostate cancer cells. WRE may offer a novel therapeutic strategy for prostate adenocarcinoma, addressing a clinical need for effective inhibitors.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Prostate adenocarcinoma pathogenesis involves increased de novo fatty acid synthesis.
- A safe and effective inhibitor of fatty acid synthesis is a clinical unmet need for prostate cancer.
- Withania somnifera is an Ayurvedic medicinal plant with potential therapeutic applications.
Purpose of the Study:
- To investigate the effect of Withania somnifera root extract (WRE) on fatty acid synthesis in human prostate cancer cells.
- To determine if WRE can inhibit key enzymes involved in fatty acid metabolism.
- To explore the potential of WRE as a novel therapeutic agent for prostate cancer.
Main Methods:
- Western blotting and confocal microscopy to assess protein levels of fatty acid metabolism enzymes.
- Quantitative real-time PCR to measure mRNA levels of key enzymes.
- Analysis of intracellular levels of acetyl-CoA, free fatty acids, and lipid droplets.
- Comparison of WRE's potency with known inhibitors like cerulenin and etomoxir.
- Investigation of c-Myc and p-Akt(S473) protein expression and their role in WRE's effects.
Main Results:
- WRE significantly decreased protein and mRNA levels of key fatty acid synthesis enzymes (ACLY, ACC1, FASN, CPT1A) in LNCaP and 22Rv1 cells.
- WRE treatment led to reduced intracellular acetyl-CoA, free fatty acids, and lipid droplets.
- WRE demonstrated higher potency in inhibiting fatty acid synthesis compared to cerulenin and etomoxir.
- WRE downregulated c-Myc and p-Akt(S473) proteins; c-Myc overexpression conferred partial protection against WRE's effects.
Conclusions:
- WRE is a novel inhibitor of fatty acid synthesis in human prostate cancer cells.
- WRE targets key enzymes in the fatty acid metabolism pathway.
- WRE, particularly withaferin A, shows therapeutic potential for prostate adenocarcinoma.
