Login to Access Video or Poster Abstract: MP88-07
Sources of Funding: None

Introduction

Although radiation therapy often with chemotherapy has been shown to offer survival rates comparable to radical cystectomy in select patients with bladder cancer, the development of radiosensitization may significantly enhance its application. Meanwhile, emerging preclinical evidence has indicated the involvement of androgen receptor (AR) signaling in urothelial cancer progression. In prostate cancer, AR has also been linked to radioresistance involving DNA repair pathways. We therefore assessed whether AR signals contribute to the sensitivity to radiotherapy in bladder cancer cells.

Methods

We compared the inhibitory effects of irradiation (2 Gy) on bladder cancer cell viability or colony formation between AR-positive [e.g. UMUC3 expressing control-short hairpin RNA (shRNA), 5637 or 647V stably expressing wild-type AR] versus AR-negative lines (e.g. UMUC3 stably expressing AR-shRNA, 5637 or 647V expressing vector only) or between AR-positive lines with versus without treatment with dihydrotestosterone (DHT) or an anti-androgen hydroxyflutamide (HF). We also compared DNA double strand breaks (DSB) via γ-H2AX foci formation in these cells after irradiation.

Results

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, DHT treatment lowered the effects of irradiation. In AR-positive cells cultured in the presence of androgens, HF treatment then enhanced the effects of irradiation. Furthermore, the percentage of cells containing >10 γ-H2AX foci in AR-negative lines was significantly higher than that in AR-positive lines after irradiation (4, 8, 12, and 24h). DSB repair was also delayed by HF treatment in AR-positive cells after irradiation (4, 8, 12, and 24h).

Conclusions

These findings suggest that AR activity correlates with the sensitivity to radiotherapy in bladder cancer cells. Accordingly, anti-androgenic drugs may function as sensitizers of irradiation, especially in patients with AR-positive urothelial cancer.

Funding

None