PEA-15/PED (Phosphoprotein enriched in astrocytes 15 kD/ Phosphoprotein enriched in diabetes) is a death effector domain-containing protein which is involved in the regulation of apoptotic cell death, insulin resistance in diabetes, and MAP kinase signaling. Since PEA-15 is highly expressed in cells of glial origin, we studied the role of PEA-15 in human malignant glioma. Immunohistochemical analysis of PEA-15 expression shows strong immunoreactivity in glioblastoma multiforme. Interestingly, immunohistochemistry with an antibody specific for phosphorylated PEA-15 (S116) results in staining of the cells in perinecrotic areas in glioblastomas, suggesting that PEA-15 is phosphorylated in response to cellular stress. Ex vivo isolated human glioblastoma cells exhibit high levels of S116-phosphorylated PEA-15. Glucose deprivation of glioblastoma cells specifically induces phosphorylation of PEA-15 at S116. Incubation of the cells with BIS-VIII, a protein kinase C inhibitor, or KN-93, a calcium/calmodulin-dependent protein kinase inhibitor, abolishes phosphorylation of PEA-15 upon glucose withdrawal. Overexpression of PEA-15 induces marked resistance against glucose deprivation-induced cell death, which is accompanied by a decreased activation of Caspase 3. Downregulation of endogenous PEA-15 by transfection of specific siRNA oligonucleotides results in sensitization to glucose withdrawal-mediated cell death and Caspase 3 cleavage. The PEA-15-dependent increase in cellular resistance to glucose deprivation is accompanied by an altered phosphorylation status of the ERK MAP kinase. Our findings suggest that PEA-15 increases the resistance of glioblastoma cells in poor microenvironments with a lack of nutrients, such as in perinecrotic areas, which possibly further hampers the efficacy of chemo- and radiotherapy.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]