title: 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.affiliation: Department of Pathology, New York University School of Medicine, New York, NY, USA.
authors.forename: Xinyu
authors.initials: X
authors.lastname: Wu
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY, USA.
authors.forename: Fangming
authors.initials: F
authors.lastname: Deng
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY, USA.
authors.forename: Yirong
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY, USA.
authors.forename: Garrett
authors.initials: G
authors.lastname: Daniels
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY, USA.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Du
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY, USA.
authors.forename: Qinghu
authors.initials: Q
authors.lastname: Ren
authors.affiliation: Department of Pediatrics, New York University School of Medicine, New York, NY, USA.|NYU Cancer Institute, New York University School of Medicine, New York, NY, USA.|NYU Center for Health Informatics and Bioinformatics, New York University School of Medicine, New York, NY, USA.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY, USA.
authors.forename: Ling Hang
authors.initials: LH
authors.lastname: Wang
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY, USA.
authors.forename: Yang
authors.initials: Y
authors.lastname: Yang
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY, USA.
authors.forename: Valerio
authors.initials: V
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: David
authors.initials: D
authors.lastname: Zhang
authors.affiliation: Department of Pathology, Mount Sinai School of Medicine, New York, NY, USA.
authors.forename: Fei
authors.initials: F
authors.lastname: Ye
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Melamed
authors.affiliation: Department of Neuroscience and Physiology, New York University School of Medicine, New York, NY, USA.|VA New York Harbor Healthcare System, New York University School of Medicine, New York, NY, USA.
authors.forename: Marie E
authors.initials: ME
authors.lastname: Monaco
authors.affiliation: Department of Pathology, New York University School of Medicine, New York, NY, USA.|NYU Cancer Institute, New York University School of Medicine, New York, NY, USA.|Department of Urology, New York University School of Medicine, New York, NY, USA.|VA New York Harbor Healthcare System, New York University School of Medicine, New York, NY, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Lee
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000818:Animals; D018931:Antineoplastic Agents, Hormonal / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003066:Coenzyme A Ligases / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm; D015971:Gene Expression Regulation, Enzymologic; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009570:Nitriles / Q000494:pharmacology; D064129:Prostatic Neoplasms, Castration-Resistant / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D034622:RNA Interference; D011944:Receptors, Androgen / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013997:Time Factors; D014105:Tosyl Compounds / Q000494:pharmacology; D014162:Transfection; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
chemical_list: C410798:AR protein, human; D000813:Anilides; D018931:Antineoplastic Agents, Hormonal; D014408:Biomarkers, Tumor; D009570:Nitriles; D011944:Receptors, Androgen; D014105:Tosyl Compounds; C053541:bicalutamide; D003066:Coenzyme A Ligases; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
keywords: ACSL4; androgen receptor; castration resistance; prostate cancer