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. ©2018 AACR.

中文翻译：

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雄激素受体信号降低膀胱癌的放射敏感性

尽管已经证明放疗通常与化疗一起提供与膀胱癌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着提高其应用。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。电离辐射比 AR 阳性细胞系更显着地减少了 AR 阴性细胞系的活细胞或集落的数量。同样，在雄激素耗尽条件下培养的 AR 阳性细胞中，二氢睾酮处理降低了辐射的影响。同时，抗雄激素羟基氟他胺在雄激素存在下培养的 AR 阳性细胞中增强了它们。AR 敲低或羟基氟他胺治疗也会导致辐射后 4-24 小时 DNA 双链断裂修复延迟。然后我们建立了“抗辐射”亚系，并发现与各自的对照相比，这些亚系中 AR 和 DNA 修复基因（如 ATR、CHEK1 和 PARP-1）的表达显着升高。此外，二氢睾酮诱导这些 DNA 修复基因在受照射的 AR 阳性细胞中表达，羟基氟他胺拮抗雄激素作用。最后，在小鼠异种移植模型中，发现低剂量氟他胺可增强照射的抑制作用，其肿瘤大小与单独放疗的 AR 敲低线相似。这些发现表明 AR 活性与膀胱癌的放射敏感性呈负相关。因此，抗雄激素药物可能起到辐射致敏剂的作用，尤其是在 AR 阳性尿路上皮癌患者中。摩尔癌症治疗; 17(7); 1566-74。©2018 AACR。