Androgen Receptor Signaling Reduces the Efficacy of Bacillus Calmette-Guerin Therapy for Bladder Cancer via Modulating Rab27b-Induced Exocytosis
Androgen Receptor Signaling Reduces the Efficacy of Bacillus Calmette-Guerin Therapy for Bladder Cancer via Modulating Rab27b-Induced Exocytosis
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DOI：
10.1158/1535-7163.mct-20-0050
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发表时间：
2020-09-01
影响因子：
5.7
通讯作者：
Miyamoto, Hiroshi
中科院分区：
文献类型：
--
作者：
Mizushima, Taichi;Jiang, Guiyang;Miyamoto, Hiroshi
虽然膀胱内卡介苗（BCG）免疫治疗已成为非肌层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抵抗，其机制尚不清楚。本研究旨在探讨雄激素受体（AR）信号是否以及如何调节BCG对膀胱癌的细胞毒作用。在膀胱癌细胞系中，AR敲低或过表达分别导致细胞内BCG量的诱导或减少及其细胞毒活性。微阵列筛选鉴定了Rab 27 b，一种已知介导细菌胞吐作用的小GTdR，其在BCG耐药细胞中上调，在AR-shRNA细胞中下调。Rab 27 b或其效应物SYTL 3的敲低或Rab 27 b的过表达也分别诱导或降低BCG量和细胞毒性。此外，用先前显示抑制Rab 27 b依赖性分泌的GW 4869处理，诱导它们并降低膀胱癌细胞中Rab 27 b的表达。同时，与相应的对照相比，BCG耐药株的AR表达上调。在小鼠原位异种移植模型中，Rab 27 b/SYTL 3敲低或GW 4869处理增强了肿瘤内BCG的量及其对肿瘤生长的抑制作用。此外，在随后接受BCG治疗的患者的非肌层浸润性膀胱癌标本中，AR/Rab 27 b表达阳性与肿瘤复发的风险显著升高相关。因此，AR激活与BCG治疗的抗性相关，推测是通过上调Rab 27 b表达。从机制上讲，这表明BCG从尿路上皮细胞中的消除是由Rab 27 b/SYTL 3介导的胞吐作用诱导的。因此，Rab 27 b失活，可能通过抗雄激素药物和/或胞吐抑制，预计将敏感BCG治疗的疗效，特别是在BCG难治性AR/Rab 27 b阳性膀胱癌患者。
Although intravesical bacillus Calmette-Guerin (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 nonmuscle-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.