Abstract C142: Functional characterization of P58IPK-PERK pathway in prostate cancer cells

Abstract

Abstract Androgen signaling is important for the normal development and function of the prostate as well as for prostate cancer (PCa). We recently found that androgens activated the IRE1α-XBP1 arm of the canonical unfolded protein response (UPR) pathways and simultaneously inhibited PERK-eIF2α signaling. Activation of the IRE1α-XBP1 arm was mediated by direct binding of the androgen receptor (AR) in the vicinity of IRE1, as well as XBP1s target genes, and increase in their expression. Consistently, AR and IRE1α pathway gene expression are correlated in human PCa samples and XBP1s protein expression is significantly increased in cancer compared to normal prostate. However, the mechanisms behind androgen mediated inhibition of PERK-eIF2α signaling are not clear at present. One possible mediator in this regard is P58IPK, an XBP1s target gene that can interact with and inhibit PERK and eIF2α phosphorylation. Here, we show that P58IPK expression is increased by androgens in a time-dependent manner and that it plays a pro-survival role in PCa cells. P58IPK knockdown activated PERK expression as well as subsequent eIF2α phosphorylation when induced with the UPR activator thapsigargin. These findings suggest that P58IPK mediates, at least in part, the differential androgen effects between the IRE1α and PERK signaling in PCa and may be a potential therapeutic target. Citation Format: Xia Sheng, Margrethe Storm, Yang Jin, Fahri Saatcioglu. Functional characterization of P58IPK-PERK pathway in prostate cancer cells. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C142.