Abstract
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.
Highlights
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)
Consistent with the reported findings that UPR activation constitutes an important component of the hypoxia response [10, 29, 30], we observed that in parallel with a higher accumulation of HIF1␣ protein (Fig. 1A), phosphorylation of inositol-requiring enzyme 1 (IRE1)␣ as well as eIF2␣ significantly increased in RKO cells in response to hypoxia (1% O2)
These results showed that hypoxic ER stress accompanied the down-regulation of -catenin signaling, suggesting that hypoxia may link the Wnt/-catenin signaling pathway to the UPR-mediated adaptive response
Summary
Hypoxia leads to activation of the UPR with simultaneously decreased -catenin signaling. Wnt3a suppressed XBP1s-mediated up-regulation of HIF1␣ target genes in CoCl2-treated RKO cells (Fig. 6C) These results indicate that Wnt/-catenin signaling could act to disrupt the cooperative activation by XBP1s–HIF1␣ of the hypoxic gene expression program. Wnt3a treatment significantly blunted the promoting effect of XBP1s upon the survival of RKO cells (Fig. 7D), and overexpression of -catenin diminished XBP1smediated improvement of survival in HEK293 cells (Fig. 7E) These data suggest that hypoxic ER stress suppression of Wnt/-catenin signaling may facilitate the efficiency of XBP1s–HIF1␣ cooperation in promoting the ability of cells to survive the hostile hypoxia environment
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