Oncotarget

Research Papers:

ACSL4 promotes prostate cancer growth, invasion and hormonal resistance

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 _ and Peng Lee

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Oncotarget. 2015; 6:44849-44863. https://doi.org/10.18632/oncotarget.6438

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Abstract

Xinyu Wu1, Fangming Deng1, Yirong Li1, Garrett Daniels1, Xinxin Du1, Qinghu Ren1, Jinhua Wang2,3,4, Ling Hang Wang1, Yang Yang1, Valerio Zhang1, David Zhang5, Fei Ye5, Jonathan Melamed1, Marie E. Monaco6,8 and Peng Lee1,3,7,8

1 Department of Pathology, New York University School of Medicine, New York, NY, USA

2 Department of Pediatrics, New York University School of Medicine, New York, NY, USA

3 NYU Cancer Institute, New York University School of Medicine, New York, NY, USA

4 NYU Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York, NY, USA

5 Department of Pathology, Mount Sinai School of Medicine, New York, NY, USA

6 Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY, USA

7 Department of Urology, New York University School of Medicine, New York, NY, USA

8 VA New York Harbor Healthcare System, New York University School of Medicine, New York, NY, USA

Correspondence to:

Marie E. Monaco, email:

Peng Lee, email:

Keywords: androgen receptor, prostate cancer, ACSL4, castration resistance

Received: March 26, 2015 Accepted: October 21, 2015 Published: November 30, 2015

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.


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