Tyrosine kinase receptor EGFR regulates the switch in cancer cells between cell survival and cell death induced by autophagy in hypoxia
| Autor: | Sara J. Israels, Daniel Huang, Spencer B. Gibson, Yongqiang Chen, Wenyan Xiao, Elizabeth S. Henson, Eileen M. McMillan-Ward |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Programmed cell death Basic Research Papers Cell Survival Caveolin 1 Models Biological Receptor tyrosine kinase 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Cell Line Tumor Autophagy medicine Humans Cell Shape Protein Kinase Inhibitors Molecular Biology biology Tyrosine phosphorylation Cell Biology BECN1 Hypoxia (medical) Cell Hypoxia Cell biology ErbB Receptors 030104 developmental biology Proto-Oncogene Proteins c-bcl-2 chemistry Gene Knockdown Techniques 030220 oncology & carcinogenesis Cancer cell biology.protein Beclin-1 medicine.symptom Oligopeptides Intracellular |
| Zdroj: | Autophagy. 12:1029-1046 |
| ISSN: | 1554-8635 1554-8627 |
| DOI: | 10.1080/15548627.2016.1164357 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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