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

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

Haemodynamic Responses to Tracheal Intubation Using Propofol, Etomidate and Etomidate-Propofol Combination in Anaesthesia Induction

Introduction: The aim of this study was to measure the haemodynamic responses to a etomidate-propofol combination used for anaesthesia induction and to compare the haemodynamic responses with the separate use of each drug. Methods: The patients were randomly divided into three groups as group P (n = 30, propofol 2.5 mg kg(-1)), group E (n = 30, etomidate 0.3 mg kg(-1)) and group PE (n = 30, propofol 1.25 mg kg(-1) + etomidate 0.15 mg kg(-1)). For each patient, the times of measurement of the heart rate (HR) and mean arterial pressure values were defined as baseline, after the induction, before the intubation, immediately after the intubation and 1, 2, 3, 4, 5 and 10 minutes after the intubation. Results: In all 3 groups, a significant decrease in MAP values were seen at T2 and T3 compared to the baseline values, and this decrease was greater in group P compared to that in group E and PE (P < 0.001, P < 0.01). A significant increase was seen in all 3 groups in the mean arterial pressure (MAP) value at T4 after the intubation. When the groups were compared with each other, this increase was greater in group E than in the other two groups (with group P, P < 0.001; with group PE, P < 0.01). Conclusion: Etomidate-propofol combination may be a valuable alternative when extremes of hypotensive and hypertensive responses due to propofol and etomidate are best to be avoided