title: Castration radiosensitizes prostate cancer tissue by impairing DNA double-strand break repair.
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.
authors.affiliation: Science 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.
authors.forename: Firas L
authors.initials: FL
authors.lastname: Tarish
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 65 Stockholm, Sweden.
authors.forename: Niklas
authors.initials: N
authors.lastname: Schultz
authors.affiliation: Department of Clinical Pathology, Uppsala University Hospital, 751 85 Uppsala, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Tanoglidi
authors.affiliation: Department of Pathology, Central Hospital, 721 89 Västerås, Sweden.
authors.forename: Hans
authors.initials: H
authors.lastname: Hamberg
authors.affiliation: Department of Oncology, Central Hospital, 721 89 Västerås, Sweden.
authors.forename: Henry
authors.initials: H
authors.lastname: Letocha
authors.affiliation: Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, OX3 9DU Oxford, UK.
authors.forename: Katalin
authors.initials: K
authors.lastname: Karaszi
authors.affiliation: Oxford Institute for Radiation Oncology, Department of Oncology, University of Oxford, OX3 9DU Oxford, UK.
authors.forename: Freddie C
authors.initials: FC
authors.lastname: Hamdy
authors.affiliation: Department of Urology, Central Hospital, 721 89 Västerås, Sweden.
authors.forename: Torvald
authors.initials: T
authors.lastname: Granfors
authors.affiliation: Science for Life Laboratory, Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 171 65 Stockholm, Sweden. thomas.helleday@scilifelab.se.
authors.forename: Thomas
authors.initials: T
authors.lastname: Helleday
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D053903:DNA Breaks, Double-Stranded; D045643:DNA Repair Enzymes / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009919:Orchiectomy; D011471:Prostatic Neoplasms / Q000235:genetics / Q000503:physiopathology / Q000532:radiotherapy*; D011836:Radiation Tolerance; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology* / Q000627:therapeutic use; D011944:Receptors, Androgen / Q000235:genetics; D055815:Young Adult
chemical_list: C410798:AR protein, human; D004268:DNA-Binding Proteins; C468783:H2AX protein, human; D006657:Histones; C508551:NHEJ1 protein, human; D011838:Radiation-Sensitizing Agents; D011944:Receptors, Androgen; D045643:DNA Repair Enzymes