Silodosin, a selective α1A-adrenergic blocker prescribed for the symptomatic treatment of
benign prostatic hyperplasia, was previously shown to decrease the expression of ELK1, a c-fos proto-oncogene regulator and a well-described downstream target of the PKC/Raf-1/ERK pathway, in human prostate smooth muscle cells. PKC/Raf-1/ERK activation has also been implicated in drug resistance. In the current study, we assessed the effects of
silodosin on ELK1 expression/activity in
bladder cancer cells as well as on their proliferation in the presence or absence of chemotherapeutic drugs, including
cisplatin and
gemcitabine. In
bladder cancer cell lines,
silodosin reduced the expression of ELK1 (
mRNA/
protein) and its downstream target, c-fos gene, as well as the transcriptional activity of ELK1. While
silodosin alone (up to 10 μM) insignificantly affected the growth of
bladder cancer cells cultured in
androgen depleted conditions or those expressing ELK1-short hairpin
RNA, it considerably inhibited the viability of
androgen receptor (AR)-positive/ELK1-positive cells in the presence of
androgens.
Silodosin also inhibited the migration of ELK1-positive cells with or without a functional AR, but not that of ELK1 knockdown cells. Interestingly,
silodosin treatment or ELK1 silencing resulted in increases in drug sensitivity to
cisplatin, but not to
gemcitabine, even in AR-negative cells or AR-positive cells cultured in an
androgen-depleted condition. In addition,
silodosin decreased the expression of NF-κB, a key regulator of chemoresistance, and its transcriptional activity. Moreover, immunohistochemistry in
bladder cancer specimens from patients who received
neoadjuvant chemotherapy revealed that phospho-ELK1 positivity strongly correlated with chemoresistance.
Silodosin was thus found to not only inhibit cell viability and migration but also enhance the cytotoxic activity of
cisplatin in
bladder cancer lines via inactivating ELK1. Our results suggest that combined treatment with
silodosin is useful for overcoming chemoresistance in patients with ELK1-positive urothelial
carcinoma receiving
cisplatin.