EGFR and EGFRvIII interact with PUMA to inhibit mitochondrial translocalization of PUMA and PUMA-mediated apoptosis independent of EGFR kinase activity

Cancer Lett. 2010 Aug 1;294(1):101-10. doi: 10.1016/j.canlet.2010.01.028. Epub 2010 Feb 13.

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.

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