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.
Bibliographical noteFunding Information:
This work is supported in part by the Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development on Biomedical Laboratory Research and Development. This study is supported by NIH 1U01CA149556-01 and DOD PCRP (PC080010 and PC11624) awards to PL, DOD BCRP Idea Award (BC084403) to MEM, NYU Molecular Oncology and Immunology Training grant (T32 CA009161) postdoctoral fellowships to GD, DOD postdoctoral fellowship (PC081578) to YRL and (PC094557) to XYW. We wish to thank the Department of Defense supported Prostate Cancer Biorepository Network (PCBN) for providing samples. NYU IHC core facility is acknowledged for IHC staining.
- Androgen receptor
- Castration resistance
- Prostate cancer