Androgen receptor variants mediate DNA repair after prostate cancer irradiation

Yi Yin, Rui Li, Kangling Xu, Sentai Ding, Jeffrey Li, Guem Hee Baek, Susmita G. Ramanand, Sam Ding, Zhao Liu, Yunpeng Gao, Mohammed S. Kanchwala, Xiangyi Li, Ryan Hutchinson, Xihui Liu, Solomon L. Woldu, Chao Xing, Neil B. Desai, Felix Y. Feng, Sandeep Burma, Johann S. De Bono & 4 others Scott M. Dehm, Ram S. Mani, Benjamin P.C. Chen, Ganesh V. Raj

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4745-4754
Number of pages10
JournalCancer Research
Volume77
Issue number18
DOIs
StatePublished - Sep 15 2017

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Androgen Receptors
DNA Repair
Prostatic Neoplasms
Androgens
DNA Damage
Radiotherapy
DNA
Therapeutics
Polynucleotide 5'-Hydroxyl-Kinase
Catalytic Domain
Cell Death
Survival

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Androgen receptor variants mediate DNA repair after prostate cancer irradiation. / Yin, Yi; Li, Rui; Xu, Kangling; Ding, Sentai; Li, Jeffrey; Baek, Guem Hee; Ramanand, Susmita G.; Ding, Sam; Liu, Zhao; Gao, Yunpeng; Kanchwala, Mohammed S.; Li, Xiangyi; Hutchinson, Ryan; Liu, Xihui; Woldu, Solomon L.; Xing, Chao; Desai, Neil B.; Feng, Felix Y.; Burma, Sandeep; De Bono, Johann S.; Dehm, Scott M.; Mani, Ram S.; Chen, Benjamin P.C.; Raj, Ganesh V.

In: Cancer Research, Vol. 77, No. 18, 15.09.2017, p. 4745-4754.

Research output: Contribution to journalArticle

Yin, Y, Li, R, Xu, K, Ding, S, Li, J, Baek, GH, Ramanand, SG, Ding, S, Liu, Z, Gao, Y, Kanchwala, MS, Li, X, Hutchinson, R, Liu, X, Woldu, SL, Xing, C, Desai, NB, Feng, FY, Burma, S, De Bono, JS, Dehm, SM, Mani, RS, Chen, BPC & Raj, GV 2017, 'Androgen receptor variants mediate DNA repair after prostate cancer irradiation', Cancer Research, vol. 77, no. 18, pp. 4745-4754. https://doi.org/10.1158/0008-5472.CAN-17-0164
Yin, Yi ; Li, Rui ; Xu, Kangling ; Ding, Sentai ; Li, Jeffrey ; Baek, Guem Hee ; Ramanand, Susmita G. ; Ding, Sam ; Liu, Zhao ; Gao, Yunpeng ; Kanchwala, Mohammed S. ; Li, Xiangyi ; Hutchinson, Ryan ; Liu, Xihui ; Woldu, Solomon L. ; Xing, Chao ; Desai, Neil B. ; Feng, Felix Y. ; Burma, Sandeep ; De Bono, Johann S. ; Dehm, Scott M. ; Mani, Ram S. ; Chen, Benjamin P.C. ; Raj, Ganesh V. / Androgen receptor variants mediate DNA repair after prostate cancer irradiation. In: Cancer Research. 2017 ; Vol. 77, No. 18. pp. 4745-4754.
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abstract = "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.",
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AU - Li, Rui

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AU - Li, Jeffrey

AU - Baek, Guem Hee

AU - Ramanand, Susmita G.

AU - Ding, Sam

AU - Liu, Zhao

AU - Gao, Yunpeng

AU - Kanchwala, Mohammed S.

AU - Li, Xiangyi

AU - Hutchinson, Ryan

AU - Liu, Xihui

AU - Woldu, Solomon L.

AU - Xing, Chao

AU - Desai, Neil B.

AU - Feng, Felix Y.

AU - Burma, Sandeep

AU - De Bono, Johann S.

AU - Dehm, Scott M.

AU - Mani, Ram S.

AU - Chen, Benjamin P.C.

AU - Raj, Ganesh V.

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