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Silodosin inhibits the growth of bladder cancer cells and enhances the cytotoxic
activity of cisplatin via ELK1 inactivation
#MMPMID26693052
Kawahara T
; Ide H
; Kashiwagi E
; Patterson JD
; Inoue S
; Shareef HK
; Aljarah AK
; Zheng Y
; Baras AS
; Miyamoto H
Am J Cancer Res
2015[]; 5
(10
): 2959-68
PMID26693052
show ga
Silodosin, a selective ?1A-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 ?M)
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-?B, 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.
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