Androgen receptor signaling reduces radiosensitivity in bladder cancer

Hiroki Ide, Satoshi Inoue, Taichi Mizushima, Guiyang Jiang, Kuang Hsiang Chuang, Mototsugu Oya, Hiroshi Miyamoto

研究成果: Article査読

13 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)1566-1574
ページ数9
ジャーナルMolecular cancer therapeutics
17
7
DOI
出版ステータスPublished - 2018 7月

ASJC Scopus subject areas

  • 腫瘍学
  • 癌研究

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