title: Divergent androgen regulation of unfolded protein response pathways drives prostate cancer.
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.
authors: Department of Biosciences, University of Oslo, Oslo, Norway.
authors: Xia
authors: X
authors: Sheng
authors: Department of Biosciences, University of Oslo, Oslo, Norway.
authors: Yke Jildouw
authors: YJ
authors: Arnoldussen
authors: Department of Biosciences, University of Oslo, Oslo, Norway.
authors: Margrethe
authors: M
authors: Storm
authors: Department of Biosciences, University of Oslo, Oslo, Norway.
authors: Martina
authors: M
authors: Tesikova
authors: Department of Biosciences, University of Oslo, Oslo, Norway.
authors: Hatice Zeynep
authors: HZ
authors: Nenseth
authors: Department of Biosciences, University of Oslo, Oslo, Norway.
authors: Sen
authors: S
authors: Zhao
authors: The Vancouver Prostate Centre, Vancouver, BC, Canada.
authors: Ladan
authors: L
authors: Fazli
authors: The Vancouver Prostate Centre, Vancouver, BC, Canada.
authors: Paul
authors: P
authors: Rennie
authors: Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway Division of Pathology, Oslo University Hospital, Oslo, Norway.
authors: Bjørn
authors: B
authors: Risberg
authors: Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway Division of Surgery, Oslo University Hospital, Oslo, Norway Center for Cancer Biomedicine, University of Oslo, Oslo, Norway.
authors: Håkon
authors: H
authors: Wæhre
authors: Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway Center for Cancer Biomedicine, University of Oslo, Oslo, Norway Department of Informatics, University of Oslo, Oslo, Norway.
authors: Håvard
authors: H
authors: Danielsen
authors: The Centre for Molecular Medicine Norway, University of Oslo, Oslo, Norway Department of Urology, Oslo University Hospital, Oslo, Norway Department of Cancer Prevention, Institute of Cancer Research, Radium Hospital, Oslo, Norway.
authors: Ian G
authors: IG
authors: Mills
authors: Department of Biosciences, University of Oslo, Oslo, Norway.
authors: Yang
authors: Y
authors: Jin
authors: Department of Genetics and Complex Diseases, Harvard School of Public Health, Harvard University, Boston, MA, USA.
authors: Gökhan
authors: G
authors: Hotamisligil
authors: Department of Biosciences, University of Oslo, Oslo, Norway Institute for Cancer Genetics and Informatics, Oslo University Hospital, Oslo, Norway fahris@ibv.uio.no.
authors: Fahri
authors: F
authors: Saatcioglu
mesh_terms: D000728:Androgens / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004722:Endoribonucleases / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000187:drug effects*; D006801:Humans; D008297:Male; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011944:Receptors, Androgen / Q000378:metabolism*; D056811:Unfolded Protein Response
chemical_list: D000728:Androgens; D011944:Receptors, Androgen; C528229:ERN1 protein, human; D017346:Protein Serine-Threonine Kinases; D004722:Endoribonucleases
keywords: ER stress; UPR; androgen receptor; androgens; prostate cancer