Abstract：
Systemic chemotherapy with gemcitabine and cisplatin (GC) has been used for the treatment of bladder cancer in which androgen receptor (AR) signaling is suggested to play a critical role. However, its efficacy is often limited, and the prognosis of patients who develop resistance is extremely poor. Aldo-keto reductase 1C3 (AKR1C3), which is responsible for the production of a potent androgen, 5α-dihydrotestosterone (DHT), by the reduction of 5α-androstane-3α,17β-dione (5α-Adione), has been attracting attention as a therapeutic target for prostate cancer that shows androgen-dependent growth. By contrast, the role of AKR1C3 in bladder cancer remains unclear. In this study, we examined the effect of an AKR1C3 inhibitor on androgen-dependent proliferation and GC sensitivity in bladder cancer cells. 5α-Adione treatment induced the expression of AR and its downstream factor ETS-domain transcription factor (ELK1) in both T24 cells and newly established GC-resistant T24GC cells, while it did not alter AKR1C3 expression. AKR1C3 inhibitor 2j significantly suppressed 5α-Adione-induced AR and ELK1 upregulation, as did an AR antagonist apalutamide. Moreover, the combination of GC and 2j in T24GC significantly induced apoptotic cell death, suggesting that 2j could enhance GC sensitivity. Immunohistochemical staining in surgical specimens further revealed that strong expression of AKR1C3 was associated with significantly higher risks of tumor progression and cancer-specific mortality in patients with muscle-invasive bladder cancer. These results suggest that AKR1C3 inhibitors as adjunctive agents enhance the efficacy of GC therapy for bladder cancer.
摘要：
吉西他滨和顺铂（GC）的全身化疗已用于治疗膀胱癌，其中雄激素受体（AR）信号传导被认为起着关键作用。然而,它的功效往往是有限的，产生耐药性的患者的预后极差。醛酮还原酶1C3（AKR1C3），负责产生强效雄激素，5α-二氢睾酮（DHT），通过还原5α-雄甾烷-3α，17β-二酮（5α-二酮），作为显示雄激素依赖性生长的前列腺癌的治疗靶标，已经引起了人们的关注。相比之下,AKR1C3在膀胱癌中的作用尚不清楚.在这项研究中,我们研究了AKR1C3抑制剂对膀胱癌细胞雄激素依赖性增殖和GC敏感性的影响.5α-Adione处理诱导T24细胞和新建立的GC抗性T24GC细胞中AR及其下游因子ETS结构域转录因子（ELK1）的表达，虽然它没有改变AKR1C3表达。AKR1C3抑制剂2j显著抑制5α-Adione诱导的AR和ELK1上调，AR拮抗剂阿帕鲁胺也是如此。此外，T24GC中GC和2j的联合显著诱导凋亡细胞死亡，表明2j可以增强GC敏感性。手术标本中的免疫组织化学染色进一步显示，AKR1C3的强表达与肌层浸润性膀胱癌患者的肿瘤进展和癌症特异性死亡率的风险显著升高相关。这些结果表明，AKR1C3抑制剂作为辅助药物可增强GC治疗膀胱癌的功效。
