Ide Hiroki, Inoue Satoshi, Mizushima Taichi, Jiang Guiyang, Nagata Yujiro, Goto Takuro, Kashiwagi Eiji, Miyamoto Hiroshi
Department of Pathology, Johns Hopkins University School of Medicine Baltimore, MD, USA.
James Buchanan Brady Urological Institute, Johns Hopkins University School of Medicine Baltimore, MD, USA.
Am J Transl Res. 2020 May 15;12(5):1779-1788. eCollection 2020.
Recent preclinical evidence has indicated that both androgen receptor (AR) inactivation and glucocorticoid receptor (GR) transrepression are associated with suppression of urothelial carcinogenesis. We therefore assessed the effect of a unique compound, 2-(4-acetoxyphenyl)-2-chloro-N-methylethylammonium chloride (Compound A; CpdA), which could function as an AR antagonist as well as a GR ligand, on urothelial tumorigenesis. Using the system with GR-positive non-neoplastic urothelial SVHUC cells stably expressing AR (SVHUC-AR), neoplastic transformation induced by a chemical carcinogen 3-methylcholanthrene (MCA) was inhibited similarly by an anti-androgen hydroxyflutamide and a glucocorticoid prednisone, and more strongly by CpdA. CpdA also prevented the neoplastic transformation of AR-negative MCA-SVHUC cells, which was diminished by a GR antagonist RU486, but failed to prevent that of GR knockdown MCA-SVHUC cells. In MCA-SVHUC-AR cells, CpdA significantly reduced the expression levels of oncogenes () and induced those of tumor suppressors (). Additionally, a potent carcinogen N-butyl-N-(4-hydroxybutyl)nitrosamine induced bladder cancer in all of 8 mock-treated mice versus 4 (50%) of flutamide-treated ( = 0.021), 4 (50%) of prednisone-treated ( = 0.021), or 2 (25%) of CpdA-treated ( = 0.002) animals. Finally, CpdA was found to reduce AR transactivation and selectively induce GR transrepression ( suppression of NF-κB transactivation and expression of its regulated genes), but not GR transactivation ( activation of glucocorticoid-response element-mediated transcription and expression of its targets) in SVHUC cells. These findings suggest that CpdA suppresses urothelial tumorigenesis via both the AR and GR pathways, which may consequently provide an effective option of chemoprevention for bladder cancer, especially in patients with superficial disease following transurethral surgery.
最近的临床前证据表明，雄激素受体（AR）失活和糖皮质激素受体（GR）反式抑制均与尿路上皮癌发生的抑制有关。因此，我们评估了一种独特的化合物2-(4-乙酰氧基苯基)-2-氯-N-甲基乙氯化铵（化合物A；CpdA）对尿路上皮肿瘤发生的影响，该化合物可作为AR拮抗剂以及GR配体发挥作用。使用稳定表达AR的GR阳性非肿瘤性尿路上皮SVHUC细胞（SVHUC-AR）体系，化学致癌物3-甲基胆蒽（MCA）诱导的肿瘤转化被抗雄激素羟基氟他胺和糖皮质激素泼尼松类似地抑制，而被CpdA更强烈地抑制。CpdA还可预防AR阴性的MCA-SVHUC细胞的肿瘤转化，该转化被GR拮抗剂RU486减弱，但不能预防GR敲低的MCA-SVHUC细胞的肿瘤转化。在MCA-SVHUC-AR细胞中，CpdA显著降低癌基因（）的表达水平并诱导肿瘤抑制因子（）的表达。此外，强效致癌物N-丁基-N-(4-羟基丁基)亚硝胺在所有8只 mock处理的小鼠中诱导膀胱癌，而在氟他胺处理的小鼠中有4只（50%）（P = 0.021）、泼尼松处理的小鼠中有4只（50%）（P = 0.021）或CpdA处理的动物中有2只（25%）（P = 0.002）发生膀胱癌。最后，发现CpdA可降低AR反式激活并选择性诱导GR反式抑制（抑制NF-κB反式激活及其调控基因的表达），但在SVHUC细胞中不诱导GR反式激活（糖皮质激素反应元件介导的转录激活及其靶标的表达）。这些发现表明，CpdA通过AR和GR途径抑制尿路上皮肿瘤发生，这可能因此为膀胱癌的化学预防提供一种有效的选择，尤其是对于经尿道手术后患有浅表疾病的患者。
