Faculty Collaboration Database

STAT5A/B Blockade Sensitizes Prostate Cancer to Radiation through Inhibition of RAD51 and DNA Repair. Clin Cancer Res 2018 Apr 15;24(8):1917-1931

Date

02/28/2018

Pubmed ID

29483142

Pubmed Central ID

PMC6036914

DOI

10.1158/1078-0432.CCR-17-2768

Scopus ID

2-s2.0-85044579498 (requires institutional sign-in at Scopus site)   42 Citations

Abstract

Purpose: The standard treatment for organ-confined prostate cancer is surgery or radiation, and locally advanced prostate cancer is typically treated with radiotherapy alone or in combination with androgen deprivation therapy. Here, we investigated whether Stat5a/b participates in regulation of double-strand DNA break repair in prostate cancer, and whether Stat5 inhibition may provide a novel strategy to sensitize prostate cancer to radiotherapy.Experimental Design: Stat5a/b regulation of DNA repair in prostate cancer was evaluated by comet and clonogenic survival assays, followed by assays specific to homologous recombination (HR) DNA repair and nonhomologous end joining (NHEJ) DNA repair. For HR DNA repair, Stat5a/b regulation of Rad51 and the mechanisms underlying the regulation were investigated in prostate cancer cells, xenograft tumors, and patient-derived prostate cancers ex vivo in 3D explant cultures. Stat5a/b induction of Rad51 and HR DNA repair and responsiveness to radiation were evaluated in vivo in mice bearing prostate cancer xenograft tumors.Results: Stat5a/b is critical for Rad51 expression in prostate cancer via Jak2-dependent mechanisms by inducing Rad51 mRNA levels. Consistent with this, genetic knockdown of Stat5a/b suppressed HR DNA repair while not affecting NHEJ DNA repair. Pharmacologic Stat5a/b inhibition potently sensitized prostate cancer cell lines and prostate cancer tumors to radiation, while not inducing radiation sensitivity in the neighboring tissues.Conclusions: This work introduces a novel concept of a pivotal role of Jak2-Stat5a/b signaling for Rad51 expression and HR DNA repair in prostate cancer. Inhibition of Jak2-Stat5a/b signaling sensitizes prostate cancer to radiation and, therefore, may provide an adjuvant therapy for radiation to reduce radiation-induced damage to the neighboring tissues. Clin Cancer Res; 24(8); 1917-31. ©2018 AACR.

Author List

Maranto C, Udhane V, Hoang DT, Gu L, Alexeev V, Malas K, Cardenas K, Brody JR, Rodeck U, Bergom C, Iczkowski KA, Jacobsohn K, See W, Schmitt SM, Nevalainen MT

Author

Kenneth Jacobsohn MD Professor in the Urologic Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Animals
Apoptosis
Cell Line, Tumor
DNA Repair
Disease Models, Animal
Gastric Mucosa
Gene Expression
Humans
Intestinal Mucosa
Male
Mice
Neoplasm Grading
Neoplasm Staging
Prostatic Neoplasms
RNA, Small Interfering
Rad51 Recombinase
Radiation Tolerance
Radiation, Ionizing
STAT5 Transcription Factor
Xenograft Model Antitumor Assays