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Sheng, X.* ; Nenseth, H.Z.* ; Qu, S.* ; Kuzu, O.F.* ; Frahnow, T. ; Simon, L. ; Greene, S.* ; Zeng, Q.* ; Fazli, L.* ; Rennie, P.S.* ; Mills, I.G.* ; Danielsen, H.* ; Theis, F.J. ; Patterson, J.B.* ; Jin, Y.* ; Saatcioglu, F.*

IRE1α-XBP1s pathway promotes prostate cancer by activating c-MYC signaling.

Nat. Commun. 10:323 (2019)
Publ. Version/Full Text Research data DOI
Open Access Gold
Creative Commons Lizenzvertrag
Activation of endoplasmic reticulum (ER) stress/the unfolded protein response (UPR) has been linked to cancer, but the molecular mechanisms are poorly understood and there is a paucity of reagents to translate this for cancer therapy. Here, we report that an IRE1 alpha RNase-specific inhibitor, MKC8866, strongly inhibits prostate cancer (PCa) tumor growth as monotherapy in multiple preclinical models in mice and shows synergistic antitumor effects with current PCa drugs. Interestingly, global transcriptomic analysis reveal that IRE1 alpha-XBP1s pathway activity is required for c-MYC signaling, one of the most highly activated oncogenic pathways in PCa. XBP1s is necessary for optimal c-MYC mRNA and protein expression, establishing, for the first time, a direct link between UPR and oncogene activation. In addition, an XBP1-specific gene expression signature is strongly associated with PCa prognosis. Our data establish IRE1 alpha-XBP1s signaling as a central pathway in PCa and indicate that its targeting may offer novel treatment strategies.
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Publication type Article: Journal article
Document type Scientific Article
Keywords Unfolded Protein Response; Endoplasmic-reticulum Stress; Transcriptional Program; Androgen Receptor; Inhibition; Antitumor; Synergy; Drives
ISSN (print) / ISBN 2041-1723
e-ISSN 2041-1723
Quellenangaben Volume: 10, Issue: 1, Pages: , Article Number: 323 Supplement: ,
Publisher Nature Publishing Group
Publishing Place London
Reviewing status Peer reviewed