STAT5A/B Blockade Sensitizes Prostate Cancer to Radiation through Inhibition of RAD51 and DNA Repair.
STAT5A/B Blockade Sensitizes Prostate Cancer to Radiation through Inhibition of RAD51 and DNA Repair.
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DOI：
10.1158/1078-0432.ccr-17-2768
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发表时间：
2018-04-15
期刊：
影响因子：
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通讯作者：
Nevalainen MT
中科院分区：
文献类型：
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作者：
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
The standard treatment for organ-confined prostate cancer (PC) is surgery or radiation, and locally advanced PC 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 PC, and whether Stat5 inhibition may provide a novel strategy to sensitize PC to radiation therapy. Stat5a/b regulation of DNA repair in PC was evaluated by comet and clonogenic survival assays, followed by assays specific to Homologous Recombination (HR) DNA repair and Non-Homologous End-Joining (NHEJ) DNA repair. For HR DNA repair, Stat5a/b regulation of Rad51 and the mechanisms underlying the regulation were investigated in PC cells, xenograft tumors and patient-derived PCs 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 PC xenograft tumors. Stat5a/b is critical for Rad51 expression in PC 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. Pharmacological Stat5a/b inhibition potently sensitized PC cell lines and PC tumors to radiation, while not inducing radiation sensitivity in the neighboring tissues. This work introduces a novel concept of a pivotal role of Jak2-Stat5a/b signaling for Rad51 expression and HR DNA repair in PC. Inhibition of Jak2-Stat5a/b signaling sensitizes PC to radiation and, therefore, may provide an adjuvant therapy for radiation to reduce radiation-induced damage to the neighboring tissues.
