Divergent androgen regulation of unfolded protein response pathways drives prostate cancer

EMBO Molecular Medicine

Xia Sheng²  Yke Jildouw Arnoldussen²  Margrethe Storm²  Martina Tesikova²  Hatice Zeynep Nenseth²  Sen Zhao²  Ladan Fazli⁵  Paul Rennie⁵  Bjørn Risberg⁴  Håkon Wæhre⁴  Håvard Danielsen⁴  Ian G Mills³  Yang Jin²  Gökhan Hotamisligil¹ 

[1] Department of Genetics and Complex Diseases, Harvard School of Public Health, Harvard University, Boston, MA, USA;Department of Biosciences, University of Oslo, Oslo, Norway;The Centre for Molecular Medicine Norway, University of Oslo, Oslo, Norway;Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway;The Vancouver Prostate Centre, Vancouver, BC, Canada

关键词: androgen receptor;    androgens;    ER stress;    prostate cancer;    UPR;   

DOI  :  10.15252/emmm.201404509

来源: Wiley

【 摘 要 】

Abstract

The unfolded protein response (UPR) is a homeostatic mechanism to maintain endoplasmic reticulum (ER) function. The UPR is activated by various physiological conditions as well as in disease states, such as cancer. As androgens regulate secretion and development of the normal prostate and drive prostate cancer (PCa) growth, they may affect UPR pathways. Here, we show that the canonical UPR pathways are directly and divergently regulated by androgens in PCa cells, through the androgen receptor (AR), which is critical for PCa survival. AR bound to gene regulatory sites and activated the IRE1α branch, but simultaneously inhibited PERK signaling. Inhibition of the IRE1α arm profoundly reduced PCa cell growth in vitro as well as tumor formation in preclinical models of PCa in vivo. Consistently, AR and UPR gene expression were correlated in human PCa, and spliced XBP-1 expression was significantly upregulated in cancer compared with normal prostate. These data establish a genetic switch orchestrated by AR that divergently regulates the UPR pathways and suggest that targeting IRE1α signaling may have therapeutic utility in PCa.

Synopsis

Androgens generate a divergent UPR response whereby the IRE1α arm is activated, and the PERK one is inhibited. Genetic depletion or small molecule inhibition of IRE1α inhibited prostate cancer cell growth in vitro and tumor.

• Androgens upregulate IRE1α signaling, but simultaneously downregulate the PERK arm of UPR.
• The effects on the IRE1α arm are mediated by direct AR binding that increases transcription of IRE1α and XBP-1S target genes.
• AR expression is correlated with UPR gene expression in human prostate cancer specimens and XBP-1S expression is increased in prostate cancer compared with normal prostate tissue.
• Inhibition of IRE1α signaling genetically or by small molecule inhibitors dramatically reduces prostate cancer growth in vitro and in vivo, suggesting that IRE1α signaling may serve as a potential therapeutic target for prostate cancer.

【 授权许可】

CC BY   
© 2015 The Authors. Published under the terms of the CC BY 4.0 license

Creative Commons Attribution 4.0 License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.