Journal
SCIENCE TRANSLATIONAL MEDICINE
Volume 7, Issue 312, Pages -Publisher
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scitranslmed.aac5671
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Funding
- Prostate Cancer UK
- Swedish Research Council
- European Research Council
- AFA insurance
- Swedish Cancer Society
- Swedish Pain Relief Foundation
- Torsten and Ragnar Soderberg Foundation
- Centre for Clinical Research (CKF)
- Vastmanland Research Foundation for Cancer in Vasteras
- Henning and Ida Persson Research Foundation
- AstraZeneca
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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 non-homologous 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 gamma-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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