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Androgen Receptor Signaling Reduces the Efficacy of Bacillus Calmette-Guérin Therapy for Bladder Cancer via Modulating Rab27b-induced Exocytosis
Molecular Cancer Therapeutics ( IF 5.7 ) Pub Date : 2020-07-31 , DOI: 10.1158/1535-7163.mct-20-0050
Taichi Mizushima 1, 2, 3, 4, 5 , Guiyang Jiang 1, 2 , Takashi Kawahara 1, 3, 4, 6 , Peng Li 3, 4 , Bin Han 3, 4 , Satoshi Inoue 1, 2, 3, 4 , Hiroki Ide 3, 4 , Ikuma Kato 7 , Mehrsa Jalalizadeh 4 , Etsuko Miyagi 5 , Mitsunori Fukuda 8 , Leonardo O Reis 3, 4 , Hiroshi Miyamoto 1, 2, 3, 4, 9
Affiliation  

Although intravesical bacillus Calmette-Guérin (BCG) immunotherapy has been the gold standard for nonsurgical management of non–muscle-invasive bladder cancer, a considerable number of patients exhibit resistance to the adjuvant treatment with unexplained mechanisms. This study aimed to investigate whether and how androgen receptor (AR) signals modulate BCG cytotoxicity in bladder cancer. AR knockdown or overexpression in bladder cancer lines resulted in induction or reduction, respectively, in intracellular BCG quantity and its cytotoxic activity. Microarray screening identified Rab27b, a small GTPase known to mediate bacterial exocytosis, which was upregulated in BCG-resistant cells and downregulated in AR-shRNA cells. Knockdown of Rab27b, or its effector SYTL3, or overexpression of Rab27b also induced or reduced, respectively, BCG quantity and cytotoxicity. In addition, treatment with GW4869, which was previously shown to inhibit Rab27b-dependent secretion, induced them and reduced Rab27b expression in bladder cancer cells. Meanwhile, AR expression was upregulated in BCG-resistant lines, compared with respective controls. In a mouse orthotopic xenograft model, Rab27b/SYTL3 knockdown or GW4869 treatment enhanced the amount of BCG within tumors and its suppressive effect on tumor growth. Moreover, in non–muscle-invasive bladder cancer specimens from patients subsequently undergoing BCG therapy, positivity of AR/Rab27b expression was associated with significantly higher risks of tumor recurrence. AR activation thus correlates with resistance to BCG treatment, presumably via upregulating Rab27b expression. Mechanistically, it is suggested that BCG elimination from urothelial cells is induced by Rab27b/SYTL3-mediated exocytosis. Accordingly, Rab27b inactivation, potentially via antiandrogenic drugs and/or exocytosis inhibition are anticipated to sensitize the efficacy of BCG therapy, especially in patients with BCG-refractory AR/Rab27b-positive bladder cancer.

中文翻译:

雄激素受体信号转导通过调节 Rab27b 诱导的胞吐作用降低卡介苗治疗膀胱癌的疗效

尽管膀胱内卡介苗 (BCG) 免疫疗法已成为非肌肉浸润性膀胱癌非手术治疗的金标准,但相当多的患者对辅助治疗表现出抗性,其机制不明。本研究旨在调查雄激素受体 (AR) 信号是否以及如何调节膀胱癌中的 BCG 细胞毒性。膀胱癌系中 AR 敲低或过表达分别导致细胞内 BCG 数量及其细胞毒活性的诱导或减少。微阵列筛选鉴定了 Rab27b,一种已知介导细菌胞吐作用的小 GTPase,它在 BCG 抗性细胞中上调,在 AR-shRNA 细胞中下调。Rab27b 或其效应子 SYTL3 的敲低,或 Rab27b 的过表达也分别诱导或减少,BCG 数量和细胞毒性。此外,用 GW4869 处理,先前显示抑制 Rab27b 依赖性分泌,诱导它们并降低膀胱癌细胞中 Rab27b 的表达。同时,与各自的对照相比,在 BCG 抗性品系中 AR 表达上调。在小鼠原位异种移植模型中,Rab27b/SYTL3 敲低或 GW4869 治疗增强了肿瘤内 BCG 的数量及其对肿瘤生长的抑制作用。此外,在随后接受卡介苗治疗的患者的非肌肉浸润性膀胱癌标本中,AR/Rab27b 表达阳性与肿瘤复发风险显着升高相关。因此,AR 激活与对 BCG 治疗的抗性相关,大概是通过上调 Rab27b 表达。从机制上讲,这表明 BCG 从尿路上皮细胞消除是由 Rab27b/SYTL3 介导的胞吐作用诱导的。因此,Rab27b 失活(可能通过抗雄激素药物和/或胞吐作用抑制)有望提高 BCG 治疗的疗效,尤其是在 BCG 难治性 AR/Rab27b 阳性膀胱癌患者中。
更新日期:2020-07-31
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