br AR signals and chemosensitivity in
AR signals and chemosensitivity in urothelial cancer A significant amount of patients with urothelial cancer fail to respond to cisplatin-based systemic chemotherapy, although it remains the mainstay of successful management of advanced disease. However, underlying mechanisms for chemoresistance remain poorly understood. Meanwhile, recent in vitro studies have strongly suggested the relationship between AR activity in urothelial cancer cells and chemosensitivity. AR-positive emca australia cancer cell lines cultured in the presence of androgens were found to be more resistant to cisplatin treatment than control AR-negative or AR knockdown cells (Kashiwagi et al., 2016b). Additionally, in AR-positive cell lines, androgen and anti-androgen treatment resulted in a decrease and an increase, respectively, in sensitivity to cisplatin. Similarly, bladder cancer cells overexpressing AR and those with DHT treatment were more resistant to doxorubicin, an anti-cancer agent often used for intravesical pharmacotherapy, than respective control cells (Shiota et al., 2012). In contrast, there were no significant differences in sensitivity to 5-fluorouracil (Shiota et al., 2012) or gemcitabine (Kashiwagi et al., 2016b) between AR-positive versus AR-negative bladder cancer lines or between AR-positive cells with versus without androgen treatment. In addition, enzalutamide treatment or AR knockdown in gemcitabine-resistant bladder cancer cells was shown to inhibit their growth, while whether it could alter chemosensitivity was not tested (Kameyama et al., 2017). More importantly, AR expression was found to be considerably elevated in “resistant” sublines established by long-term culture with cisplatin (Kashiwagi et al., 2016b), doxorubicin (Shiota et al., 2012), or gemcitabine (Kameyama et al., 2017), compared with respective control cells. Immunohistochemistry in bladder cancer specimens from patients who subsequently underwent cisplatin-based neoadjuvant chemotherapy also revealed a strong trend to correlate between AR positivity and chemoresistance (21% of responders vs. 45% of non-responders, P = 0.087) (Kashiwagi et al., 2016b). Therefore, AR inactivation is anticipated to enhance the cytotoxic activity of certain anti-cancer agents in urothelial cancer cells. NF-κB activation has been implicated in the acquisition of cisplatin resistance (Ito et al., 2015). Indeed, the expression levels of NF-κB and phospho-NF-κB, an active form of NF-κB, were strikingly higher in the cisplatin-resistant bladder cancer sublines than in respective control sublines (Kashiwagi et al., 2016b). Additionally, in the bladder cancer specimens described above (Kashiwagi et al., 2016b), phospho-NF-κB positivity was also associated with cisplatin resistance (54% of responders vs. 81% of non-responders, P = 0.044). Moreover, androgen treatment induced the expression of NF-κB and phospho-NF-κB as well as nuclear translocation of NF-κB in AR-positive bladder cancer cells (Kashiwagi et al., 2016b). Interestingly, ELK1 inactivation via its shRNA expression or silodosin treatment was also found to increase sensitivity to cisplatin, but not gemcitabine, as well as reduce the expression and transcriptional activity of NF-κB, similarly in AR-positive versus AR-negative bladder cancer cells (Kawahara et al., 2015a). Because phospho-ELK1 positivity in the tissue specimens was strongly associated with cisplatin resistance (38% of responders vs. 71% of non-responders, P = 0.039) (Kawahara et al., 2015a), the effects of androgen/AR on chemosensitivity might be mediated at least partially via ELK1 signaling.
AR co-regulators in urothelial cancer As aforementioned, androgen-mediated AR transcriptional activity is further modulated by co-regulators (Rahman et al., 2004). Several AR co-regulators have indeed been suggested to involve urothelial cancer cell growth. A cross-talk between AR co-regulators and other signaling pathways has also been documented in bladder cancer cells, which may further modulate urothelial tumorigenesis and tumor progression.