Divergent androgen regulation of unfolded protein response pathways drives prostate cancer
| Autor: | Ian G. Mills, Yang Jin, Xia Sheng, Paul S. Rennie, Gökhan S. Hotamisligil, Margrethe Storm, Håvard E. Danielsen, Hatice Zeynep Nenseth, Björn Risberg, Sen Zhao, Martina Tesikova, Fahri Saatcioglu, Ladan Fazli, Yke Jildouw Arnoldussen, Haakon Wæhre |
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| Rok vydání: | 2015 |
| Předmět: |
Male
medicine.medical_specialty endocrine system UPR Biology Protein Serine-Threonine Kinases urologic and male genital diseases Prostate cancer SDG 3 - Good Health and Well-being Downregulation and upregulation Internal medicine Cell Line Tumor androgen receptor Endoribonucleases medicine Humans Research Articles Cell Proliferation Regulation of gene expression Cell growth Endoplasmic reticulum Cancer androgens medicine.disease prostate cancer Cell biology Androgen receptor Endocrinology Gene Expression Regulation Receptors Androgen Unfolded protein response Unfolded Protein Response Molecular Medicine ER stress |
| Zdroj: | EMBO Molecular Medicine Sheng, X, Arnoldussen, Y J, Storm, M, Tesikova, M, Nenseth, H Z, Zhao, S, Fazli, L, Rennie, P, Risberg, B, Wæhre, H, Danielsen, H, Mills, I G, Jin, Y, Hotamisligil, G & Saatcioglu, F 2015, ' Divergent androgen regulation of unfolded protein response pathways drives prostate cancer ', EMBO Molecular Medicine, vol. 7, no. 6, pp. 788-801 . https://doi.org/10.15252/emmm.201404509 |
| ISSN: | 1757-4684 1757-4676 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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