Androgen receptor activity modulates responses to cisplatin treatment in bladder cancer.
Cisplatin (CDDP)-based combination chemotherapy remains the mainstream treatment for advanced bladder cancer. However, its efficacy is often limited due to the development of resistance for which underlying mechanisms are poorly understood. Meanwhile, emerging evidence has indicated the involvement of androgen-mediated androgen receptor (AR) signals in bladder cancer progression. In this study, we aimed to investigate whether AR signals have an impact on sensitivity to CDDP in bladder cancer cells. UMUC3-control-short hairpin RNA (shRNA) cells with endogenous AR and AR-negative 647V/5637 cells stably expressing AR were significantly more resistant to CDDP treatment at its pharmacological concentrations, compared with UMUC3-AR-shRNA and 647V-vector/5637-vector control cells, respectively. A synthetic androgen R1881 significantly reduced CDDP sensitivity in UMUC3, 647V-AR, or 5637-AR cells, and the addition of an anti-androgen hydroxyflutamide inhibited the effect of R1881. In these AR-positive cells, R1881 treatment also induced the expression levels of NF-κB, which is known to involve CDDP resistance, and its phosphorylated form, as well as nuclear translocation of NF-κB. In CDDP-resistant bladder cancer sublines established following long-term culture with CDDP, the expression levels of AR as well as NF-κB and phospho-NF-κB were considerably elevated, compared with respective control sublines. In bladder cancer specimens, there was a strong trend to correlate between AR positivity and chemoresistance. These results suggest that AR activation correlates with CDDP resistance presumably via modulating NF-κB activity in bladder cancer cells. Targeting AR during chemotherapy may thus be a useful strategy to overcome CDDP resistance in patients with AR-positive bladder cancer.
Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Eiji
E
Kashiwagi
Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Hiroki
H
Ide
Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Satoshi
S
Inoue
Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Takashi
T
Kawahara
Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Yichun
Y
Zheng
Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Leonardo O
LO
Reis
Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Alexander S
AS
Baras
Departments of Pathology and Urology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Hiroshi
H
Miyamoto
D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D016328:NF-kappa B / Q000378:metabolism*; D010766:Phosphorylation; D034741:RNA, Small Interfering / Q000378:metabolism; D011944:Receptors, Androgen / Q000378:metabolism*; D015398:Signal Transduction; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology
D016328:NF-kappa B; D034741:RNA, Small Interfering; D011944:Receptors, Androgen; D002945:Cisplatin
NF-κB; androgen receptor; bladder cancer; chemoresistance; cisplatin