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Cyproterone Acetate Enhances TRAIL‐induced Androgen‐independent Prostate Cancer Cell Apoptosis via Upregulation of Death Receptor 5
Author(s) -
Chen Linjie,
Wolff Dennis W.,
Xie Yan,
Lin MingFong,
Tu Yaping
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.670.7
Subject(s) - androgen receptor , du145 , cyproterone acetate , prostate cancer , cancer research , apoptosis , lncap , chemistry , microbiology and biotechnology , biology , medicine , endocrinology , androgen , cancer , biochemistry , hormone
Objective Virtually all prostate cancer deaths occur due to obtaining the castration‐resistant phenotype after prostate cancer cells escaped from the apoptosis and/or growth suppression initially induced by androgen receptor blockade. TNF‐related apoptosis‐inducing ligand (TRAIL) was an attractive cancer therapeutic agent due to its minimal toxicity to normal cells and remarkable apoptotic activity in tumor cells. However, most localized cancers including prostate cancer are resistant to TRAIL‐induced apoptosis, thereby creating a therapeutic challenge of inducing TRAIL sensitivity in cancer cells. Herein the effects of cyproterone acetate, an antiandrogen steroid, on the TRAIL‐induced apoptosis of androgen receptor‐negative prostate cancer cells are reported. Methods Cell apoptosis was assessed by both annexin V/propidium iodide labeling and poly (ADP‐ribose) polymerase cleavage assays. Changes of gene expression were determined by western blot and RT‐PCR assays. The effect of cyproterone acetate on the gene promoter activity was determined by luciferase reporter assay. Results Cyproterone acetate dramatically increased the susceptibility of androgen receptor‐negative prostate cancer PC‐3 and DU145 cells to TRAIL‐induced apoptosis. Further investigation of the TRAIL‐induced apoptosis pathway revealed that cyproterone acetate exerted its effect by selectively increasing death receptor 5 (DR5) expression. Cyproterone acetate treatment increased DR5 gene promoter activity, which could be abolished by mutation of a consensus binding domain of transcription factor CCAAT‐enhancer‐binding protein homologous protein (CHOP) in the DR5 gene promoter. Cyproterone acetate increased CHOP expression by inducing endoplasmic reticulum (ER) stress / unfolded protein response (UPR) and siRNA silencing of CHOP significantly reduced cyproterone acetate ‐induced DR5 upregulation and TRAIL sensitivity in prostate cancer cells. Conclusion Together, our study shows a novel effect of cyproterone acetate on prostate cancer cell apoptosis pathways and raises the possibility that a combination of TRAIL with cyproterone acetate could be a promising strategy for treating castration‐resistant prostate cancer. Support or Funding Information This work was supported by grants from the National Institutes of Health (5P20GM103489 and R01HL116849), Nebraska State LB595 research program.