The online version of this article (doi:10.1186/s12885-017-3153-4) contains supplementary material, which is available to authorized users.
Virtually all prostate cancer deaths occur due to obtaining the castration-resistant phenotype after prostate cancer cells escaped from 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.
Cell apoptosis was assessed by both annexin V/propidium iodide labeling and poly (ADP-ribose) polymerase cleavage assays. Gene and protein expression changes were determined by quantitative real-time PCR and western blot assays. The effect of cyproterone acetate on gene promoter activity was determined by luciferase reporter assay.
Cyproterone acetate but not AR antagonist bicalutamide dramatically increased the susceptibility of androgen receptor-negative human prostate cancer PC-3 and DU145 cells to TRAIL-induced apoptosis but no effects on immortalized human prostate stromal PS30 cells and human embryonic kidney HEK293 cells. Further investigation of the TRAIL-induced apoptosis pathway revealed that cyproterone acetate exerted its effect by selectively increasing death receptor 5 (DR5) mRNA and protein expression. Cyproterone acetate treatment also 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 increases CHOP expression in a concentration and time-dependent manner and endoplasmic reticulum stress reducer 4-phenylbutyrate could block cyproterone acetate-induced CHOP and DR5 up-regulation. More importantly, siRNA silencing of CHOP significantly reduced cyproterone acetate-induced DR5 up-regulation and TRAIL sensitivity in prostate cancer cells.
Our study shows a novel effect of cyproterone acetate on apoptosis pathways in prostate cancer cells and raises the possibility that a combination of TRAIL with cyproterone acetate could be a promising strategy for treating castration-resistant prostate cancer.
Additional file 2: Figure S1. CPA treatment had no effects on DR5 expression or TRAIL sensitivity in human embryonic kidney HEK293 cells. Cells were pretreated with or without 50 μM CPA for 24 h, and then treated with or without 50 ng/ml TRAIL for 6 h. Cells were harvested and subjected to western blot analysis of DR5 expression and cleavage of PARP. β-actin was used as a loading control. Data shown are means ± S.E. (n = 3). Inset: Representative western blot images of PARP, DR5 and β-actin. (JPG 475 kb)
Torri V, Floriani I. Cyproterone acetate in the therapy of prostate carcinoma. Arch Ital Urol Androl. 2005;77:157–63. PubMed
Scott WW, Menon M, Walsh PC. Hormonal therapy of prostatic cancer. Cancer. 1980;45(Suppl):1929–36. PubMed
Forero-Torres A, Infante JR, Waterhouse D, Wong L, Vickers S, Arrowsmith E, et al. Phase 2, multicenter, open-label study of tigatuzumab (CS-1008), a humanized monoclonal antibody targeting death receptor 5, in combination with gemcitabine in chemotherapy-naive patients with unresectable or metastatic pancreatic cancer. Cancer Med. 2013;2:925–32. CrossRefPubMedPubMedCentral
Forero-Torres A, Varley KE, Abramson VG, Li Y, Vaklavas C, Lin NU, et al. TBCRC 019: a phase II trial of nanoparticle albumin-bound paclitaxel with or without the anti-death receptor 5 monoclonal antibody tigatuzumab in patients with triple-negative breast cancer. Clin Cancer Res. 2015;21:2722–9. CrossRefPubMed
- Cyproterone acetate enhances TRAIL-induced androgen-independent prostate cancer cell apoptosis via up-regulation of death receptor 5
Dennis W. Wolff
- BioMed Central
Neu im Fachgebiet Onkologie
Mail Icon II