EGFR and EGFRvIII undergo stress- and EGFR kinase inhibitor-induced mitochondrial translocalization: A potential mechanism of EGFR-driven antagonism of apoptosis

Molecular Cancer

Research

Xinyu Cao¹  Hu Zhu²  Francis Ali-Osman³  Hui-Wen Lo³ 

[1] Division of Surgical Sciences, Department of Surgery, Duke University School of Medicine, 433A MSRB I, 103 Research Drive, 27710, Durham, NC, USA;Division of Surgical Sciences, Department of Surgery, Duke University School of Medicine, 433A MSRB I, 103 Research Drive, 27710, Durham, NC, USA;Department of Pharmacology, University of North Carolina-Chapel Hill, Box 7365, 27599, Chapel Hill, NC, USA;Division of Surgical Sciences, Department of Surgery, Duke University School of Medicine, 433A MSRB I, 103 Research Drive, 27710, Durham, NC, USA;Duke Comprehensive Cancer Center, 27710, Durham, NC, USA;Preston Robert Tisch Brain Tumor Center at Duke University, 27710, Durham, NC, USA;

关键词: Epidermal Growth Factor Receptor;    Staurosporine;    Epidermal Growth Factor Receptor Inhibitor;    Epidermal Growth Factor Receptor Signaling;    T98G Cell;   

DOI  :  10.1186/1476-4598-10-26

 received in 2010-09-23, accepted in 2011-03-09,  发布年份 2011

来源: Springer

【 摘 要 】

BackgroundEpidermal growth factor receptor (EGFR) plays an essential role in normal development, tumorigenesis and malignant biology of human cancers, and is known to undergo intracellular trafficking to subcellular organelles. Although several studies have shown that EGFR translocates into the mitochondria in cancer cells, it remains unclear whether mitochondrially localized EGFR has an impact on the cells and whether EGFRvIII, a constitutively activated variant of EGFR, undergoes mitochondrial transport similar to EGFR.ResultsWe report that both receptors translocate into the mitochondria of human glioblastoma and breast cancer cells, following treatments with the apoptosis inducers, staurosporine and anisomycin, and with an EGFR kinase inhibitor. Using mutant EGFR/EGFRvIII receptors engineered to undergo enriched intracellular trafficking into the mitochondria, we showed that glioblastoma cells expressing the mitochondrially enriched EGFRvIII were more resistant to staurosporine- and anisomycin-induced growth suppression and apoptosis and were highly resistant to EGFR kinase inhibitor-mediated growth inhibition.ConclusionsThese findings indicate that apoptosis inducers and EGFR-targeted inhibitors enhance mitochondrial translocalization of both EGFR and EGFRvIII and that mitochondrial accumulation of these receptors contributes to tumor drug resistance. The findings also provide evidence for a potential link between the mitochondrial EGFR pathway and apoptosis.

【 授权许可】

Unknown   
© Cao et al; licensee BioMed Central Ltd. 2011. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.