Abstract
EGFR and its constitutively activated variant EGFRvIII are linked to glioblastoma resistance to therapy, the mechanisms underlying this association, however, are still unclear. We report that in glioblastoma, EGFR/EGFRvIII paradoxically co-expresses with p53-upregulated modulator of apoptosis (PUMA), a proapoptotic member of the Bcl-2 family of proteins primarily located on the mitochondria. EGFR/EGFRvIII binds to PUMA constitutively and under apoptotic stress, and subsequently sequesters PUMA in the cytoplasm. The EGFR-PUMA interaction is independent of EGFR activation and is sustained under EGFR inhibition. A Bcl-2/Bcl-xL inhibitor that mimics PUMA activity sensitizes EGFR/EGFRvIII-expressing glioblastoma cells to Iressa. Collectively, we uncovered a novel kinase-independent function of EGFR/EGFRvIII that leads to tumor drug resistance.
Copyright (c) 2010 Elsevier Ireland Ltd. All rights reserved.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
MeSH terms
-
Antineoplastic Agents / pharmacology
-
Antineoplastic Agents / therapeutic use
-
Apoptosis / physiology*
-
Apoptosis Regulatory Proteins / metabolism*
-
Astrocytoma / genetics
-
Astrocytoma / metabolism
-
Brain Neoplasms / drug therapy
-
Brain Neoplasms / genetics
-
Brain Neoplasms / metabolism*
-
Breast Neoplasms / genetics
-
Breast Neoplasms / metabolism
-
Cell Line, Tumor
-
Cell Survival / drug effects
-
DNA Transposable Elements
-
ErbB Receptors / genetics
-
ErbB Receptors / metabolism*
-
Female
-
Gefitinib
-
Genetic Variation
-
Glioblastoma / drug therapy
-
Glioblastoma / genetics
-
Glioblastoma / metabolism*
-
Humans
-
Mitochondria / metabolism*
-
Proto-Oncogene Proteins / metabolism*
-
Quinazolines / pharmacology
-
Quinazolines / therapeutic use
-
Sequence Deletion
-
Transplantation, Heterologous
Substances
-
Antineoplastic Agents
-
Apoptosis Regulatory Proteins
-
BBC3 protein, human
-
DNA Transposable Elements
-
Proto-Oncogene Proteins
-
Quinazolines
-
epidermal growth factor receptor VIII
-
ErbB Receptors
-
Gefitinib