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.
Highlights
Androgen ablation therapy remains the standard of treatment for recurrent and metastatic PCa, most cases treated with ablation therapy will evolve into castration-resistant prostate cancer (CRPC), the primary cause of prostate cancer-related death
When ACSL4 expression in LNCaP-AI cells was abolished by treatment with small interfering RNA (siRNA), the expression of androgen receptor (AR) was increased (Figure 1D)
We studied the expression of ACSL4 protein in human PCa tissue samples by immunohistochemical analysis of a human PCa tissue microarray (TMA) derived from a cohort of PCa patients (n = 155) in various clinicopathological groups and benign prostate tissue (n = 124)
Summary
Androgen ablation therapy remains the standard of treatment for recurrent and metastatic PCa, most cases treated with ablation therapy will evolve into castration-resistant prostate cancer (CRPC), the primary cause of prostate cancer-related death. We and others have demonstrated that forced expression of ACSL4 in ER-positive MCF7 cells results in increased proliferation, migration and invasion in vitro as well as increased growth in in vivo xenograft models [10,11,12]. These data raise the question of the function of ACSL4 enzyme activity in mediating the aggressive phenotype associated with hormone independence in PCa
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