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Castration radiosensitizes prostate cancer tissue by impairing DNA double-strand break repair

Science Translational Medicine  04 Nov 2015:
Vol. 7, Issue 312, pp. 312re11
DOI: 10.1126/scitranslmed.aac5671

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Giving radiotherapy a boost

Androgen deprivation therapy (castration) combined with radiotherapy improves the overall response to radiotherapy in patients with localized intermediate- and high-risk prostate cancer. In a new study, Tarish et al. biopsied prostate cancer patients at diagnosis and before and after castration and radiotherapy treatments to monitor the molecular events that might explain this improved response. They found that castration impaired DNA double-strand break repair specifically in prostate cancer tissue. This correlated with an increase in unrepaired DNA double-strand breaks caused by radiotherapy, explaining how castration improved the response to radiotherapy. These findings provide mechanistic insight into why castration improves the overall response to radiotherapy in prostate cancer patients.

Abstract

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.

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