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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited Authors

  • Zhu, H; Cao, X; Ali-Osman, F; Keir, S; Lo, H-W

Published Date

  • August 1, 2010

Published In

Volume / Issue

  • 294 / 1

Start / End Page

  • 101 - 110

PubMed ID

  • 20153921

Pubmed Central ID

  • PMC2875288

Electronic International Standard Serial Number (EISSN)

  • 1872-7980

Digital Object Identifier (DOI)

  • 10.1016/j.canlet.2010.01.028


  • eng

Conference Location

  • Ireland