title: Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia.
abstract: Autophagy is an intracellular lysosomal degradation pathway where its primary function is to allow cells to survive under stressful conditions. Autophagy is, however, a double-edge sword that can either promote cell survival or cell death. In cancer, hypoxic regions contribute to poor prognosis due to the ability of cancer cells to adapt to hypoxia in part through autophagy. In contrast, autophagy could contribute to hypoxia induced cell death in cancer cells. In this study, we showed that autophagy increased during hypoxia. At 4 h of hypoxia, autophagy promoted cell survival whereas, after 48 h of hypoxia, autophagy increased cell death. Furthermore, we found that the tyrosine phosphorylation of EGFR (epidermal growth factor receptor) decreased after 16 h in hypoxia. Furthermore, EGFR binding to BECN1 in hypoxia was significantly higher at 4 h compared to 72 h. Knocking down or inhibiting EGFR resulted in an increase in autophagy contributing to increased cell death under hypoxia. In contrast, when EGFR was reactivated by the addition of EGF, the level of autophagy was reduced which led to decreased cell death. Hypoxia led to autophagic degradation of the lipid raft protein CAV1 (caveolin 1) that is known to bind and activate EGFR in a ligand-independent manner during hypoxia. By knocking down CAV1, the amount of EGFR phosphorylation was decreased in hypoxia and amount of autophagy and cell death increased. This indicates that the activation of EGFR plays a critical role in the switch between cell survival and cell death induced by autophagy in hypoxia.
authors.affiliation: a Research Institute in Oncology and Hematology, CancerCare Manitoba , Winnipeg , Manitoba , Canada.
authors.forename: Yongqiang
authors.initials: Y
authors.lastname: Chen
authors.affiliation: a Research Institute in Oncology and Hematology, CancerCare Manitoba , Winnipeg , Manitoba , Canada.|b Department of Biochemistry and Medical Genetics , University of Manitoba , Winnipeg , Manitoba , Canada.
authors.forename: Elizabeth S
authors.initials: ES
authors.lastname: Henson
authors.affiliation: a Research Institute in Oncology and Hematology, CancerCare Manitoba , Winnipeg , Manitoba , Canada.
authors.forename: Wenyan
authors.initials: W
authors.lastname: Xiao
authors.affiliation: a Research Institute in Oncology and Hematology, CancerCare Manitoba , Winnipeg , Manitoba , Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Huang
authors.affiliation: a Research Institute in Oncology and Hematology, CancerCare Manitoba , Winnipeg , Manitoba , Canada.
authors.forename: Eileen M
authors.initials: EM
authors.lastname: McMillan-Ward
authors.affiliation: a Research Institute in Oncology and Hematology, CancerCare Manitoba , Winnipeg , Manitoba , Canada.|c Department of Pediatrics , University of Manitoba , Winnipeg , Manitoba , Canada.
authors.forename: Sara J
authors.initials: SJ
authors.lastname: Israels
authors.affiliation: a Research Institute in Oncology and Hematology, CancerCare Manitoba , Winnipeg , Manitoba , Canada.|b Department of Biochemistry and Medical Genetics , University of Manitoba , Winnipeg , Manitoba , Canada.
authors.forename: Spencer B
authors.initials: SB
authors.lastname: Gibson
mesh_terms: D001343:Autophagy / Q000187:drug effects; D000071186:Beclin-1 / Q000378:metabolism; D051242:Caveolin 1 / Q000378:metabolism; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D048430:Cell Shape / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D066246:ErbB Receptors / Q000378:metabolism*; D055785:Gene Knockdown Techniques; D006801:Humans; D008954:Models, Biological; D009842:Oligopeptides / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism
chemical_list: C491997:BECN1 protein, human; D000071186:Beclin-1; C495540:CAV1 protein, human; D051242:Caveolin 1; D009842:Oligopeptides; D047428:Protein Kinase Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; C517629:benzyloxycarbonyl-valyl-alanyl-aspartic acid; D066246:ErbB Receptors
keywords: Autophagy; CAV1 (caveolin-1); autosis; cell death; epidermal growth factor receptor (EGFR); hypoxia