ELK1 promotes urothelial tumorigenesis in the presence of an activated androgen receptor.

We have recently demonstrated that ELK1, a transcription factor that triggers downstream targets including c-Fos proto-oncogene, promotes the growth of bladder cancer cells possessing a functional androgen receptor (AR). We here assessed the function of ELK1, as well as the efficacy of a selective α1A-adrenergic blocker silodosin that has been shown to inhibit ELK1 activity in bladder cancer cells, in urothelial tumorigenesis. The level of ELK1 expression in an immortalized normal urothelial cell line SVHUC stably expressing wild-type AR (SVHUC-AR) was considerably higher than that in AR-negative SVHUC-vector cells, which was induced further or reduced by dihydrotestosterone or silodosin treatment, respectively. In SVHUC-AR cells exposed to a chemical carcinogen 3-methylcholanthrene, silodosin significantly reduced the expression levels of oncogenes (e.g. c-Fos, Jun, Myc), as well as phospho-p38 MAPK and phospho-ERK proteins, and increased those of tumor suppressor genes (e.g. p53, PTEN, UGT1A). ELK1 suppression via ELK1-short hairpin RNA virus infection or silodosin treatment also resulted in significant inhibition in 3-methylcholanthrene-induced neoplastic transformation of SVHUC-AR cells, but not that of SVHUC-vector cells. In N-butyl-N-(4-hydroxybutyl)nitrosamine-treated male C57BL/6 mice, the incidence rate of bladder tumors was significantly (P = 0.007) lower in the silodosin group than in the control group. ELK1 thus appears to play a critical role in urothelial tumorigenesis, and silodosin prevents it presumably via down-regulation of ELK1. Moreover, ELK1 may require an activated AR for inducing neoplastic transformation of urothelial cells. Our findings may therefore offer a novel chemopreventive approach, via ELK1 inactivation using silodosin treatment, for bladder cancer.