128 - RelB-BLNK axis: a novel determinant of cell fate

Abstract

Prostate cancer (PCa), the second leading cause of male cancer deaths in the United States, is most frequently treated with radiation therapy (RT). We screened 786 FDA-approved compounds to identify drugs that can radiosensitize PCa cells while radioprotecting non-cancer prostate epithelial cells and identified Betamethasone (BET) as a lead compound with these properties. BET increases ROS levels in PCa cells (high oxidized redox state) but not in normal prostate epithelial cells (low oxidized redox state). Remarkably, BET has an opposite effect on RelB, a non-canonical redox-sensitive NF-κB pathway. BET suppresses the expression of RelB and RelB target genes including MnSOD and survivin in PCa cells, while it induces expression of RelB and MnSOD in non-cancer cells. The differential effects of BET are, in part, attributable to the intrinsic differences in the cellular redox states of normal versus PCa cells. Intriguingly, RNA seq and ChIP assays identify B-cell linker protein (BLNK) as a novel RelB transcription regulator that is differentially regulated by BET in normal and cancer cells. Proximity-ligation assays and knockdown of BLNK confirm that RelB-BLNK possibly interact in the nuclear compartment. BET/RT treatments that target disruptions of RelB and BLNK expressions reverse the survival of PCa cells but not of normal prostate epithelial cells. Our study is the first to establish that the RelB-BLNK mediated NF-κB non-canonical pathway is a novel mechanism to regulate the differential responses to radiation therapy of normal prostate epithelial and prostate cancer cells. The results of this study fill in a critical gap in scientific knowledge of how the differences in redox conditions of normal and tumor cells trigger differential responses to pro-oxidants. They will facilitate the translation of therapeutic approaches that use prooxidants to push cancer cells into oxidative stress overload but stimulate adaptive responses in normal cells to selectively enhance RT efficacy.