Androgen Receptor Variants Mediate DNA Repair after Prostate Cancer Irradiation.

Autor:	Yin Y; Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas. Yi.Yin@utsouthwestern.edu Ganesh.Raj@utsouthwestern.edu., Li R; Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas., Xu K; Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas., Ding S; Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.; Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, P.R. China., Li J; Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas., Baek G; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas., Ramanand SG; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas., Ding S; Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas., Liu Z; Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.; Department of Urology, Shandong Provincial Hospital Affiliated to Shandong University, Jinan, Shandong, P.R. China., Gao Y; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas., Kanchwala MS; Eugene McDermott Center for Human Growth & Development, University of Texas Southwestern Medical Center, Dallas, Texas., Li X; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas., Hutchinson R; Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas., Liu X; Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas., Woldu SL; Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas., Xing C; Eugene McDermott Center for Human Growth & Development, University of Texas Southwestern Medical Center, Dallas, Texas., Desai NB; Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas., Feng FY; Department of Radiation Oncology, University of California at San Francisco, San Francisco, California.; Department of Urology, University of California at San Francisco, San Francisco, California.; Department of Medicine, University of California at San Francisco, San Francisco, California., Burma S; Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas., de Bono JS; Drug Development Unit and Prostate Cancer Targeted Therapy Group, The Royal Marsden NHS Foundation Trust and The Institute of Cancer Research, London, United Kingdom., Dehm SM; Masonic Cancer Center and Departments of Laboratory Medicine and Pathology and Urology, University of Minnesota, Minneapolis, Minnesota., Mani RS; Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas., Chen BPC; Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas., Raj GV; Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas. Yi.Yin@utsouthwestern.edu Ganesh.Raj@utsouthwestern.edu.; Department of Pharmacology, University of Texas Southwestern Medical Center, Dallas, Texas.
Jazyk:	angličtina
Zdroj:	Cancer research [Cancer Res] 2017 Sep 15; Vol. 77 (18), pp. 4745-4754. Date of Electronic Publication: 2017 Jul 28.
DOI:	10.1158/0008-5472.CAN-17-0164
Abstrakt:	In prostate cancer, androgen deprivation therapy (ADT) enhances the cytotoxic effects of radiotherapy. This effect is associated with weakening of the DNA damage response (DDR) normally supported by the androgen receptor. As a significant number of patients will fail combined ADT and radiotherapy, we hypothesized that DDR may be driven by androgen receptor splice variants (ARV) induced by ADT. Investigating this hypothesis, we found that ARVs increase the clonogenic survival of prostate cancer cells after irradiation in an ADT-independent manner. Notably, prostate cancer cell irradiation triggers binding of ARV to the catalytic subunit of the critical DNA repair kinase DNA-PK. Pharmacologic inhibition of DNA-PKc blocked this interaction, increased DNA damage, and elevated prostate cancer cell death after irradiation. Our findings provide a mechanistic rationale for therapeutic targeting of DNA-PK in the context of combined ADT and radiotherapy as a strategy to radiosensitize clinically localized prostate cancer. Cancer Res; 77(18); 4745-54. ©2017 AACR . (©2017 American Association for Cancer Research.)
Databáze:	MEDLINE
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