STAT5A/B Blockade Sensitizes Prostate Cancer to Radiation through Inhibition of RAD51 and DNA Repair

Abstract

Purpose: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.Experimental Design: Stat5a/b regulation of DNA repair in PC was evaluated by comet and clonogenic TRANSLATIONAL RELEVANCERadiation therapy is a key treatment option for both organ-confined and locally advanced prostate cancer (PC). However, irradiation is often associated with significant toxicities to the neighboring tissues, which can cause debilitating side-effects. In the present study, we demonstrated proof-ofconcept that targeting Stat5a/b signaling sensitizes PC to radiation through regulation of DNA repair.Our results provide, for the first time, mechanistic evidence that Jak2-Stat5a/b signaling is critical for Rad51 expression and Homologous-Recombination DNA repair in PC. Using human PC cell lines, xenograft tumors and ex vivo culture of clinical PCs, we show that genetic or pharmacological inhibition of Stat5a/b sensitizes PC to irradiation while not affecting the radiation sensitivity of the surrounding tissues. These findings provide a strong rationale for development of Stat5a/b inhibitors as adjuvant therapy for radiation treatment of PC.Research.on April 28,

Neutrophils are mediators of metastatic prostate cancer progression in bone

“…bone metastatic PCa where siRNA-mediated STAT5 inhibition significantly increased PCa Caspase 7 expression and apoptosis [25,28]. Additional studies showed that STAT5 expression is increased in aggressive prostate cancer and inhibition of STAT5 was able to sensitize BM-PCa xenografts to radiation through blockade of STAT5-mediated DNA repair [29,30]. Our studies revealed that neutrophilmediated PCa death is due to specific inhibition of STAT5 expression supporting prior evidence that STAT5 is a potential target for preventing progression of aggressive, metastatic PCa.…”

A functional genomics screen reveals a strong synergistic effect between docetaxel and the mitotic gene DLGAP5 that is mediated by the androgen receptor

“…1e , panel bottom right). RAD51 is a DNA damage response gene that has been associated with resistance to radiation and PARP inhibitors in PCa, and is co-regulated by p53 15 – 17 . Overall, the GI assay in DMSO detected both known PCa associated genes, as well as an interesting candidate not previously associated with PCa ( DTL ).…”

Prospects for Clinical Development of Stat5 Inhibitor IST5-002: High Transcriptomic Specificity in Prostate Cancer and Low Toxicity In Vivo

“…By targeting Stat5, IST5 has been shown to have high efficacy in cell-based model systems of cancer [10,24,47]. A substantial body of work supports the concept that Stat5 is critical for PC cell viability in vitro and xenograft tumor growth in vivo , and IST5 has been shown to induce extensive apoptotic death of PC cells, block growth of PC xenograft tumors in mice in vivo [2][3][4][6][7][8]10,14,15,47], and induce apoptotic death in patient-derived clinical PCs ex vivo in 3D tumor explant cultures [10,47].…”