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

  • Research Article
  • Published:
Tumor Biology

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.

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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

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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.

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None

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Authors and Affiliations

  1. Institute of Neuropathology, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany

    Agnieszka Dreier, Anand Goswami & Joachim Weis

  2. Institute of Biomedical Engineering, Division of Experimental Medicine and Immunotherapy, Medical Faculty, RWTH Aachen University, Pauwelsstr. 30, 52074, Aachen, Germany

    Stefan Barth

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  1. Agnieszka Dreier
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Correspondence to Agnieszka Dreier.

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Dreier, A., Barth, S., Goswami, A. et al. Cetuximab induces mitochondrial translocalization of EGFRvIII, but not EGFR: involvement of mitochondria in tumor drug resistance?. Tumor Biol. 33, 85–94 (2012). https://doi.org/10.1007/s13277-011-0248-4

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