Hypoxic Er Stress Suppresses β-catenin Expression And Promotes Cooperation Between The Transcription Factors XBP1 And HIF1α For Cell Survival

WNT/β-catenin signaling plays a key role in regulating embryonic development,tissue homeostasis and tumorigenesis.Most colorectal cancers(CRC)are initiated by the aberrant activation of Wnt pathway characterized by the accumulation of cytoplasimicβ-catenin.Hypoxia,a hallmark of most solid tumors,occurs in many human solid tumors and elicits activation of multiple cellular adaptive response pathways,including the unfolded protein response(UPR)at 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(HIF1α)-activated gene expression profile,thereby promoting cell survival during hypoxia.However,the molecular interplays between hypoxic ER stress,Wnt/β-catenin signaling and HIF1α-mediated gene regulation during hypoxia remain incompletely understood.In the present study,we demonstrated that the hypoxic microenvironmental stresses existed in the solid tumor are able to destabilize β-catenin and inhibit the canonical WNT/β-catenin signaling pathway.The low-density lipoprotein receptor-related protein-6(LRP6),expressed in various human cancer cell lines and malignant tumors,is an essential Wnt co-receptor for transmission of Wnt signaling.Here,we revealed both LRP6 andβ-catenin protein levels would significantly be decreased under 1% oxygen condition compared with normal oxygen in RKO cells.As previously reported hypoxia(1% oxygen)could disturb the homeostasis of ER capacity hypoxic tumor microenvironment(TME)disturbs the protein-folding capacity of endoplasmic reticulum(ER),ecliting ER tress and triggering the unfolded protein response(UPR)thereby provoking ER stress.Morever,we found that hypoxia-induced ER stress reduces LRP6 expression and further blocksβ-catenin accumulation in cytoplasm.Unexpectly,overexpression of LRP6ΔN,a constitutive active form of LRP6,could totally reverse the degradation of β-catenin induced by hypoxia.In addition,Wnt/β-catenin signaling could negatively regulate the downstream signaling mediatey by XBP1 s and HIF1α.And the activity Wnt signaling could counter cells survival aroused by XBP1 s.Taken together,these findings contribute to our deep understanding of β-catenin regulation in hypoxic tumor microenvironment and uncover a new regulatory mechanism of HIF1α mediated adaptive response.Collectively,our data suggest that this UPR adaptive processes are essential for cell survival under hypoxic stress and that the IRE1α/XBP1 pathway could be a promising target for treating hypoxic circumstances,especillay in tumor environment.