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Chemical castration improves responses to radiotherapy in prostate cancer, but the mechanism is unknown. We hypothesized that this radiosensitization is caused by castration-mediated down-regulation of nonhomologous end joining (NHEJ) repair of DNA double-strand breaks (DSBs). To test this, we enrolled 48 patients with localized prostate cancer in two arms of the study: either radiotherapy first or radiotherapy after neoadjuvant castration treatment. We biopsied patients at diagnosis and before and after castration and radiotherapy treatments to monitor androgen receptor, NHEJ, and DSB repair in verified cancer tissue. We show that patients receiving neoadjuvant castration treatment before radiotherapy had reduced amounts of the NHEJ protein Ku70, impaired radiotherapy-induced NHEJ activity, and higher amounts of unrepaired DSBs, measured by γ-H2AX foci in cancer tissues. This study demonstrates that chemical castration impairs NHEJ activity in prostate cancer tissue, explaining the improved response of patients with prostate cancer to radiotherapy after chemical castration.

Original publication

DOI

10.1126/scitranslmed.aac5671

Type

Journal article

Journal

Sci Transl Med

Publication Date

04/11/2015

Volume

7

Keywords

Adult, Aged, Aged, 80 and over, DNA Breaks, Double-Stranded, DNA Repair Enzymes, DNA-Binding Proteins, Gene Expression Regulation, Neoplastic, Histones, Humans, Male, Middle Aged, Orchiectomy, Prostatic Neoplasms, Radiation Tolerance, Radiation-Sensitizing Agents, Receptors, Androgen, Young Adult