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Tumor Biology

, Volume 33, Issue 1, pp 85–94 | Cite as

Cetuximab induces mitochondrial translocalization of EGFRvIII, but not EGFR: involvement of mitochondria in tumor drug resistance?

  • Agnieszka Dreier
  • Stefan Barth
  • Anand Goswami
  • Joachim Weis
Research Article

Abstract

Dysregulation of growth factor receptors such as the epidermal growth factor receptor (EGFR) and of its truncated form EGFRvIII is frequently found in human tumors. EGFRvIII is a promising target for selective molecular tumor therapy because it is exclusively expressed by tumor cells. Cetuximab/Erbitux is a monoclonal antibody which targets EGFR and EGFRvIII. The effects of cetuximab on EGFRvIII but still the exact function and mechanism of cetuximab in relation to EGFR and EGFRvIII are incompletely understood. Therefore, we investigated the influence of cetuximab on EGFRvIII signaling and cellular survival. We found that cetuximab leads to increased internalization of EGFRvIII in NR6M cells but is unable to inhibit neither the activation of EGFRvIII nor its downstream signaling pathways. Incubation with cetuximab also did not alter the survival and proliferation of EGFRvIII-expressing cells. However, it caused increased mitochondrial activity and an increase in co-localization of EGFRvIII with mitochondria. These results demonstrate that interaction of EGFRvIII with mitochondria could play a role in survival of cetuximab-treated NR6M cells. Thus, a role of mitochondria in resistance to cetuximab has to be considered.

Keywords

EGFR EGFRvIII Cetuximab Mitochondria Tumor drug resistance 

Abbreviations

Akt

Anti-apoptotic kinase

BrdU

5-Bromo-2′-deoxyuridine

Cet

Cetuximab

CytC

Cytochrome C

EGF

Epidermal growth factor

EGFR

Epidermal growth factor receptor (wild type receptor)

EGFRvIII/de2-7 EGFR/∆EGFR

EGFR variant three (mutant receptor)

Erk

Extracellular signal-regulated kinase

MAPK

Mitogen-activated protein kinase

STAT

Signal transducer and activator of transcription

TGF-α

Transforming growth factor alpha

Tim23

Subunit of mitochondrial inner membrane translocase complex

Notes

Acknowledgments

We thank Dr. D. Bigner, Duke University, Durham, NC, USA, for supplying the NR6, NR6W, and NR6M cells; Dr. B. Lüscher, Institute of Biochemistry; and Dr. S. Arnold, Institute of Neuroanatomy, both RWTH Aachen University, for helpful discussions, and PD Dr. G. Brook, Institute of Neuropathology, RWTH Aachen University, for reading the manuscript.

Funding

This study was funded by the START program “Molecular tumor markers and their function,” Medical Faculty, RWTH Aachen University, Aachen, Germany.

Conflicts of interest

None

Supplementary material

13277_2011_248_MOESM1_ESM.pdf (5.2 mb)
ESM 1 (PDF 5.18 mb)

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Copyright information

© International Society of Oncology and BioMarkers (ISOBM) 2011

Authors and Affiliations

  • Agnieszka Dreier
    • 1
  • Stefan Barth
    • 2
  • Anand Goswami
    • 1
  • Joachim Weis
    • 1
  1. 1.Institute of Neuropathology, Medical FacultyRWTH Aachen UniversityAachenGermany
  2. 2.Institute of Biomedical Engineering, Division of Experimental Medicine and Immunotherapy, Medical FacultyRWTH Aachen UniversityAachenGermany

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