Inhibition of Epidermal Growth Factor Receptor Signaling Protects Human Malignant Glioma Cells from Hypoxia-Induced Cell Death

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Abstract
Epidermal growth factor receptor (EGFR) signaling has become an important target for drug development because EGFR signaling enhances tumor cell proliferation, migration, and invasion and inhibits apoptosis. However, the results of clinical trials using EGFR inhibitors in patients with solid tumors have been disappointing. Here, we report a protective effect of the EGFR inhibitors AG1478 and PD153035 against cell death induced by acute hypoxia, which contrasts with their proapoptotic effects under normoxia. Under hypoxic conditions, both agents reduced glucose consumption, delayed ATP depletion, and preserved the mitochondrial membrane potential. Exposure either to hypoxia or the EGFR inhibitors under normoxic conditions resulted in the dephosphorylation of ribosomal protein S6, a player in the energy and nutrient-sensing pathway governed by mammalian target-of-rapamycin (mTOR). Combined inhibition of phosphatidylinositol 3′-kinase (PI3K) and extracellular signal-regulated kinase-1/2 (ERK1/2) mimicked the protective effects of EGFR inhibition on hypoxia-induced cell death and protein S6 dephosphorylation. These results caution that therapies targeting EGFR signaling pathways can protect tumor cells from acute hypoxia.