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 IRE1α 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 IRE1α-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 IRE1α-XBP1s signaling as a central pathway in PCa and indicate that its targeting may offer novel treatment strategies.

中文翻译：

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IRE1α-XBP1s途径通过激活c-MYC信号传导来促进前列腺癌。

内质网（ER）应激的激活/未折叠的蛋白质反应（UPR）与癌症有关，但是对分子机制的了解甚少，并且缺乏用于癌症治疗的试剂。在这里，我们报道IRE1αRNase特异性抑制剂MKC8866作为单一疗法在小鼠的多个临床前模型中强烈抑制前列腺癌（PCa）肿瘤的生长，并显示与当前PCa药物的协同抗肿瘤作用。有趣的是，全球转录组学分析表明，IREA1-XBP1s途径活性是c-MYC信号传导所必需的，而c-MYC信号传导是PCa中活化程度最高的致癌途径之一。XBP1s对于最佳c-MYC mRNA和蛋白质表达是必不可少的，这是首次在UPR和致癌基因激活之间建立直接联系。此外，XBP1特异性基因表达特征与PCa的预后密切相关。我们的数据将IRE1α-XBP1s信号确立为PCa的主要途径，并表明其靶向可能提供新颖的治疗策略。