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

Firas L Tarish1, Niklas Schultz2, Anna Tanoglidi3

  • 1Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 65 Stockholm, Sweden. Department of Urology, Central Hospital, 721 89 Västerås, Sweden.

Science Translational Medicine
|November 6, 2015
PubMed

Insights

Chemical castration enhances radiotherapy effectiveness in prostate cancer by reducing DNA repair. This treatment lowers nonhomologous end joining (NHEJ) activity, leading to more unrepaired DNA damage and better treatment outcomes.

Area of Science:

  • Oncology
  • Radiation Oncology
  • Molecular Biology

Background:

  • Chemical castration is known to improve radiotherapy outcomes in prostate cancer patients.
  • The underlying mechanism for this radiosensitization effect remains largely unknown.
  • Nonhomologous end joining (NHEJ) is a primary pathway for repairing DNA double-strand breaks (DSBs) induced by radiotherapy.

Purpose of the Study:

  • To investigate the hypothesis that chemical castration radiosensitizes prostate cancer by down-regulating NHEJ repair of DSBs.
  • To elucidate the molecular mechanisms linking castration, DNA repair, and radiotherapy response in prostate cancer.

Main Methods:

  • A study involving 48 patients with localized prostate cancer was conducted.
  • Patients were assigned to two arms: radiotherapy first or radiotherapy after neoadjuvant castration.
  • Biopsies were taken at diagnosis, pre- and post-castration, and post-radiotherapy to assess androgen receptor, NHEJ activity, and DSB repair markers (e.g., γ-H2AX foci).

Main Results:

  • Neoadjuvant chemical castration significantly reduced the NHEJ protein Ku70 in prostate cancer tissues.
  • Castration impaired radiotherapy-induced NHEJ activity.
  • Higher levels of unrepaired DSBs, indicated by increased γ-H2AX foci, were observed in patients receiving castration before radiotherapy.

Conclusions:

  • Chemical castration impairs the nonhomologous end joining (NHEJ) DNA repair pathway in prostate cancer cells.
  • This impairment of NHEJ activity by castration contributes to the radiosensitization observed in prostate cancer patients.
  • The findings provide a molecular explanation for improved radiotherapy responses following neoadjuvant chemical castration.

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