Divergent androgen regulation of unfolded protein response pathways drives prostate cancer.
Divergent androgen regulation of unfolded protein response pathways drives prostate cancer.
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DOI：
10.15252/emmm.201404509
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发表时间：
2015-06
影响因子：
11.1
通讯作者：
Saatcioglu F
中科院分区：
文献类型：
--
作者：
Sheng X;Arnoldussen YJ;Storm M;Tesikova M;Nenseth HZ;Zhao S;Fazli L;Rennie P;Risberg B;Wæhre H;Danielsen H;Mills IG;Jin Y;Hotamisligil G;Saatcioglu F
未折叠蛋白反应（UPR）是维持内质网（ER）功能的稳态机制。普遍定期审查被各种生理条件以及疾病状态（如癌症）激活。由于雄激素调节正常前列腺的分泌和发育并驱动前列腺癌（PCa）的生长，它们可能影响UPR通路。在这里，我们发现雄激素通过雄激素受体（AR）直接和分散地调节PCa细胞中的典型UPR通路，雄激素受体（AR）对PCa的存活至关重要。AR结合到基因调控位点并激活IRE1α分支，但同时抑制PERK信号。IRE1α臂的抑制显著降低了体外PCa细胞的生长以及体内PCa临床前模型的肿瘤形成。与此一致，AR和UPR基因在人前列腺癌中的表达是相关的，并且与正常前列腺相比，剪接的XBP-1在癌中的表达显著上调。这些数据建立了一个由AR协调的基因开关，该开关可对UPR通路进行差异化调节，并表明靶向IRE1α信号通路可能具有治疗PCa的效用。
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.
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DOI：
10.1074/jbc.m109.014092
发表时间：
2010-02-26
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Armstrong JL;Flockhart R;Veal GJ;Lovat PE;Redfern CP
通讯作者：
Redfern CP
影响因子：
3.4
作者：
Bluemn EG;Nelson PS
通讯作者：
Nelson PS
影响因子：
16
作者：
Kroemer G;Mariño G;Levine B
通讯作者：
Levine B
DOI：
10.1073/pnas.1304318110
发表时间：
2013-07-09
影响因子：
11.1
作者：
Jin, Yang;Qu, Su;Saatcioglu, Fahri
通讯作者：
Saatcioglu, Fahri
影响因子：
10.5
作者：
Nishitoh, H;Matsuzawa, A;Ichijo, H
通讯作者：
Ichijo, H