The PEA-15 PED protein protects glioblastoma cells from glucose deprivation-induced apoptosis via the ERK MAP kinase pathway

• Published in: Oncogene Vol. 27; no. 8; pp. 1155 - 1166
• Main Authors: ECKERT, A, BÖCK, B. C, WIESTLER, O. D, WALCZAK, H, ROTH, W, TAGSCHERER, K. E, HAAS, T. L, GRUND, K, SYKORA, J, HEROLD-MENDE, C, EHEMANN, V, HOLLSTEIN, M, CHNEIWEISS, H
• Format: Journal Article
• Language: English
• Published: Basingstoke Nature Publishing 14.02.2008; Nature Publishing Group
• Subjects: Ageing, cell death; Animals; Apoptosis; Apoptosis - physiology; Astrocytes; Astrocytoma; Biological and medical sciences; Brain cancer; Brain Neoplasms - enzymology; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain tumors; Care and treatment; Causes of; Cell death; Cell Line, Tumor; Cell physiology; Cell Survival; Cell transformation and carcinogenesis. Action of oncogenes and antioncogenes; Extracellular signal-regulated kinase; Extracellular Signal-Regulated MAP Kinases - physiology; Fundamental and applied biological sciences. Psychology; Genetic aspects; Glioblastoma; Glioblastoma - enzymology; Glioblastoma - metabolism; Glioblastoma - pathology; Glioblastoma cells; Glioblastoma multiforme; Glioma cells; Glucose; Glucose - deficiency; Glucose - metabolism; Glucose transporter; Humans; Immunoreactivity; Intracellular Signaling Peptides and Proteins - genetics; Intracellular Signaling Peptides and Proteins - physiology; Kinases; Male; MAP kinase; MAP Kinase Signaling System - physiology; Medical sciences; Mice; Mice, Nude; Microenvironments; Molecular and cellular biology; Neurology; Oncology; Phosphoproteins - biosynthesis; Phosphoproteins - genetics; Phosphoproteins - physiology; Phosphorylation; Physiological aspects; Protein kinases; Risk factors; Signal transduction; siRNA; Transcription; Tumorigenicity; Tumors of the nervous system. Phacomatoses; Germany; Nervous system diseases; Extracellular signal-regulated protein kinase; Enzyme; Transferases; Glioblastoma; Mitogen-activated protein kinase; Malignant tumor; Glucose; Carcinogenesis; Intracranial tumor; PEA-15/PED; Protein; Cerebral disorder; Malignant glioma; ERK1/2; brain tumors; Central nervous system disease; MAP kinases; Cancer; Apoptosis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/sj.onc.1210732

PEA-15 (phosphoprotein enriched in astrocytes 15 kDa) is a death effector domain-containing protein, which is involved in the regulation of apoptotic cell death. Since PEA-15 is highly expressed in cells of glial origin, we studied the role of PEA-15 in human malignant brain tumors. Immunohistochemical analysis of PEA-15 expression shows strong immunoreactivity in astrocytomas and glioblastomas. Phosphorylation of PEA-15 at Ser(116) is found in vivo in perinecrotic areas in glioblastomas and in vitro after glucose deprivation of glioblastoma cells. Overexpression of PEA-15 induces a marked resistance against glucose deprivation-induced apoptosis, whereas small interfering RNA (siRNA)-mediated downregulation of endogenous PEA-15 results in the sensitization to glucose withdrawal-mediated cell death. This antiapoptotic activity of PEA-15 under low glucose conditions depends on its phosphorylation at Ser(116). Moreover, siRNA-mediated knockdown of PEA-15 abolishes the tumorigenicity of U87MG glioblastoma cells in vivo. PEA-15 regulates the level of phosphorylated extracellular-regulated kinase (ERK)1/2 in glioblastoma cells and the PEA-15-dependent protection from glucose deprivation-induced cell death requires ERK1/2 signaling. PEA-15 transcriptionally upregulates the Glucose Transporter 3, which is abrogated by the inhibition of ERK1/2 phosphorylation. Taken together, our findings suggest that Ser(116)-phosphorylated PEA-15 renders glioma cells resistant to glucose deprivation-mediated cell death as encountered in poor microenvironments, for example in perinecrotic areas of glioblastomas.