Identification of pY654-β-catenin as a critical co-factor in hypoxia-inducible factor-1α signaling and tumor responses to hypoxia.

摘要: Hypoxia is linked to epithelial-mesenchymal transition (EMT) and tumor progression in numerous carcinomas. Responses hypoxia are thought operate via hypoxia-inducible factors (HIFs), but the importance of co-factors that regulate HIF signaling within tumors not well understood. Here, we elucidate a pathway physically functionally couples tyrosine phosphorylation β-catenin HIF1α HIF1α-mediated EMT. Primary human lung adenocarcinomas accumulate pY654-β-catenin HIF1α. All pY654-β-catenin, only phosphorylated form, was found complexed with active Src, both cell lines exposed hypoxia. Phosphorylation Y654, generated by mediated, reactive oxygen species (ROS)-dependent Src kinase activation, required for interact promote transcriptional activity, hypoxia-induced Mice bearing hypoxic pancreatic islet adenomas, treatment anti-vascular endothelial growth factor antibodies, HIF1α/pY654-β-catenin complexes develop an invasive phenotype. Concurrent administration ROS inhibitor N-acetylcysteine abrogated β-catenin/HIF activity restored adenoma architecture. Collectively, findings implicate accumulation specifically as critically involved invasion. The also suggest targeting ROS-dependent aspects pY654-β-catenin/ may attenuate untoward biological effects anti-angiogenic agents