Cellular Signaling Laboratory, International Research Center for Sensory Biology and Technology of MOST, Key Laboratory of Molecular Biophysics of MOE, and College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, China.
Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, Institute for Advanced Studies, Wuhan University, Wuhan 430072, China.
J Biol Chem. 2019 Sep 13;294(37):13811-13821. doi: 10.1074/jbc.RA119.008353. Epub 2019 Jul 26.
Hypoxia occurs in many human solid tumors and activates multiple cellular adaptive-response pathways, including the unfolded protein response (UPR) in the endoplasmic reticulum (ER). Wnt/β-catenin signaling plays a critical role in tumorigenesis, and β-catenin has been shown to enhance hypoxia-inducible factor 1α (HIF1α)-activated gene expression, thereby supporting cell survival during hypoxia. However, the molecular interplay between hypoxic ER stress, Wnt/β-catenin signaling, and HIF1α-mediated gene regulation during hypoxia remains incompletely understood. Here, we report that hypoxic ER stress reduces β-catenin stability, which, in turn, enhances the activity of spliced X-box-binding protein 1 (XBP1s), a transcription factor and signal transducer of the UPR, in HIF1α-mediated hypoxic responses. We observed that in the RKO colon cancer cell line, which possesses a Wnt-stimulated β-catenin signaling cascade, increased ER stress during hypoxia is accompanied by a reduction in low-density lipoprotein receptor-related protein 6 (LRP6), and this reduction in LRP6 decreased β-catenin accumulation and impaired Wnt/β-catenin signaling. Of note, β-catenin interacted with both XBP1s and HIF1α, suppressing XBP1s-mediated augmentation of HIF1α target gene expression. Furthermore, Wnt stimulation or β-catenin overexpression blunted XBP1s-mediated cell survival under hypoxia. Together, these results reveal an unanticipated role for the Wnt/β-catenin pathway in hindering hypoxic UPR-mediated responses that increase cell survival. Our findings suggest that the molecular cross-talks between hypoxic ER stress, LRP6/β-catenin signaling, and the HIF1α pathway may represent an unappreciated mechanism that enables some tumor subtypes to survive and grow in hypoxic conditions.
缺氧发生于许多人类实体肿瘤中，并激活多种细胞适应性反应途径，包括内质网（ER）中的未折叠蛋白反应（UPR）。Wnt/β-catenin 信号通路在肿瘤发生中起着关键作用，并且已经表明β-catenin 增强了缺氧诱导因子 1α（HIF1α）激活的基因表达，从而在缺氧期间支持细胞存活。然而，缺氧 ER 应激、Wnt/β-catenin 信号通路和 HIF1α介导的基因调控之间的分子相互作用在很大程度上仍未得到理解。在这里，我们报告说，缺氧 ER 应激会降低β-catenin 的稳定性，这反过来又增强了 HIF1α介导的缺氧反应中 UPR 的转录因子和信号转导物剪接 X 盒结合蛋白 1（XBP1s）的活性。我们观察到，在具有 Wnt 刺激的β-catenin 信号级联的 RKO 结肠癌细胞系中，缺氧期间 ER 应激的增加伴随着低密度脂蛋白受体相关蛋白 6（LRP6）的减少，而 LRP6 的减少降低了β-catenin 的积累并损害了 Wnt/β-catenin 信号通路。值得注意的是，β-catenin 与 XBP1s 和 HIF1α相互作用，抑制了 XBP1s 介导的 HIF1α 靶基因表达的增强。此外，Wnt 刺激或β-catenin 过表达在缺氧下削弱了 XBP1s 介导的细胞存活。总之，这些结果揭示了 Wnt/β-catenin 通路在阻止增加细胞存活的缺氧 UPR 介导反应中出人意料的作用。我们的发现表明，缺氧 ER 应激、LRP6/β-catenin 信号通路和 HIF1α 通路之间的分子相互作用可能代表一种未被认识的机制，使某些肿瘤亚型能够在缺氧条件下存活和生长。
