ACSL4 promotes prostate cancer growth, invasion and hormonal resistance.

Abstract

Increases in fatty acid metabolism have been demonstrated to promote the growth and survival of a variety of cancers, including prostate cancer (PCa). Here, we examine the expression and function of the fatty acid activating enzyme, long-chain fatty acyl-CoA synthetase 4 (ACSL4), in PCa. Ectopic expression of ACSL4 in ACSL4-negative PCa cells increases proliferation, migration and invasion, while ablation of ACSL4 in PCa cells expressing endogenous ACSL4 reduces cell proliferation, migration and invasion. The cell proliferative effects were observed both in vitro, as well as in vivo. Immunohistochemical analysis of human PCa tissue samples indicated ACSL4 expression is increased in malignant cells compared with adjacent benign epithelial cells, and particularly increased in castration-resistant PCa (CRPC) when compared with hormone naive PCa. In cell lines co-expressing both ACSL4 and AR, proliferation was independent of exogenous androgens, suggesting that ACSL4 expression may lead to CRPC. In support for this hypothesis, ectopic ACSL4 expression induced resistance to treatment with Casodex, via decrease in apoptosis. Our studies further indicate that ACSL4 upregulates distinct pathway proteins including p-AKT, LSD1 and β-catenin. These results suggest ACSL4 could serve as a biomarker and potential therapeutic target for CRPC.

• Authors: Xinyu Wu, Fangming Deng, Yirong Li, Garrett Daniels, Xinxin Du, Qinghu Ren, Jinhua Wang, Ling Hang Wang, Yang Yang, Valerio Zhang, David Zhang, Fei Ye, Jonathan Melamed, Marie E Monaco, Peng Lee
• Journal: Oncotarget (Oncotarget) Vol. 6 Issue 42 Pg. 44849-63 (Dec 29 2015) ISSN: 1949-2553 [Electronic] United States
• PMID: 26636648 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• AR protein, human
• Anilides
• Antineoplastic Agents, Hormonal
• Biomarkers, Tumor
• Nitriles
• Receptors, Androgen
• Tosyl Compounds
• bicalutamide
• Coenzyme A Ligases
• long-chain-fatty-acid-CoA ligase

Topics

• Anilides (pharmacology)
• Animals
• Antineoplastic Agents, Hormonal (pharmacology)
• Apoptosis (drug effects)
• Biomarkers, Tumor (genetics, metabolism)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Coenzyme A Ligases (genetics, metabolism)
• Drug Resistance, Neoplasm
• Gene Expression Regulation, Enzymologic
• Gene Expression Regulation, Neoplastic
• Humans
• Male
• Mice, Nude
• Neoplasm Invasiveness
• Nitriles (pharmacology)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, enzymology, genetics, pathology)
• RNA Interference
• Receptors, Androgen (genetics, metabolism)
• Signal Transduction
• Time Factors
• Tosyl Compounds (pharmacology)
• Transfection
• Up-Regulation
• Xenograft Model Antitumor Assays