Androgen Receptor Signaling Reduces Radiosensitivity in Bladder Cancer
Androgen Receptor Signaling Reduces Radiosensitivity in Bladder Cancer
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DOI：
10.1158/1535-7163.mct-17-1061
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发表时间：
2018-07-01
影响因子：
5.7
通讯作者：
Miyamoto, Hiroshi
中科院分区：
文献类型：
--
作者：
Ide, Hiroki;Inoue, Satoshi;Miyamoto, Hiroshi
虽然放射治疗通常配合化疗在特定的膀胱癌患者中提供了与根治性膀胱切除术相当的生存益处，但放射增敏策略的发展可能会显著加强其应用。值得注意的是，新出现的临床前证据表明雄激素受体(AR)信号参与了尿路上皮癌的进展。我们在这里评估了AR信号是否有助于调节膀胱癌细胞的放射敏感性。与AR阳性株系相比，电离辐射使AR阴性株系的活细胞数或菌落数显著减少。同样，在雄激素耗竭条件下培养的AR阳性细胞中，双氢睾酮处理降低了辐射的影响。同时，在雄激素存在下培养的AR阳性细胞中，抗雄激素羟基氟他胺增强了它们的表达。AR基因敲除或羟基氟他胺处理也导致照射后4-24小时DNA双链断裂修复延迟。然后，我们建立了抗辐射的亚系，并发现与各自的对照相比，AR和DNA修复基因如ATR、CHEK1和PARP-1的表达都有相当大的提高。此外，双氢睾酮可诱导辐射后AR阳性细胞中这些DNA修复基因的表达，羟基氟他胺可拮抗雄激素的作用。最后，在小鼠异种移植模型中，低剂量氟他胺被发现增强了辐射的抑制作用，其肿瘤大小与单纯辐射的AR基因敲除线相似。这些发现表明，在膀胱癌中，AR活性与放射敏感性呈负相关。因此，抗雄激素药物可能起到辐射增敏的作用，特别是在AR阳性的尿路上皮癌患者中。摩尔癌症杂志；17(7)；1566-74。(C)2018年AACR。
Although radiotherapy often with chemotherapy has been shown to offer a survival benefit comparable with that of radical cystectomy in select patients with bladder cancer, the development of radiosensitization strategies may significantly enhance its application. Notably, emerging preclinical evidence has indicated the involvement of androgen receptor (AR) signaling in urothelial cancer progression. We here assessed whether AR signals could contribute to modulating radiosensitivity in bladder cancer cells. Ionizing radiation reduced the numbers of viable cells or colonies of AR-negative lines more significantly than those of AR-positive lines. Similarly, in AR-positive cells cultured in androgen-depleted conditions, dihydrotestosterone treatment lowered the effects of irradiation. Meanwhile, an antiandrogen hydroxyflutamide enhanced them in AR-positive cells cultured in the presence of androgens. AR knockdown or hydroxyflutamide treatment also resulted in a delay in DNA double-strand break repair 4-24 hours after irradiation. We then established "radiation-resistant" sublines and found considerable elevation of the expression of AR as well as DNA repair genes, such as ATR, CHEK1, and PARP-1, in these sublines, compared with respective controls. Furthermore, dihydrotestosterone induced the expression of these DNA repair genes in irradiated AR-positive cells, and hydroxyflutamide antagonized the androgen effects. Finally, in a mouse xenograft model, low-dose flutamide was found to enhance the inhibitory effects of irradiation, and its tumor size was similar to that of AR knockdown line with radiation alone. These findings suggest that AR activity inversely correlates with radiosensitivity in bladder cancer. Accordingly, antiandrogenic drugs may function as sensitizers of irradiation, especially in patients with AR-positive urothelial cancer. Mol Cancer Ther; 17(7); 1566-74. (C) 2018 AACR.