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Neoplasia. 2016 Feb;18(2):111-20. doi: 10.1016/j.neo.2016.01.002.

Ezrin Enhances EGFR Signaling and Modulates Erlotinib Sensitivity in Non-Small Cell Lung Cancer Cells.

Author information

1
Department of Oncology, Georgetown University Medical Center, Washington, DC, USA; Department of Molecular Medicine, Institute of Health Sciences, Dokuz Eylul University, Izmir, Turkey.
2
Department of Oncology, Georgetown University Medical Center, Washington, DC, USA.
3
Department of Medical Biology, Dokuz Eylul University School of Medicine, Izmir, Turkey.
4
Department of Oncology, Georgetown University Medical Center, Washington, DC, USA. Electronic address: au26@georgetown.edu.

Abstract

Ezrin is a scaffolding protein that is involved in oncogenesis by linking cytoskeletal and membrane proteins. Ezrin interacts with epidermal growth factor receptor (EGFR) in the cell membrane, but little is known about the effects of this interaction on EGFR signaling pathway. In this study, we established the biological and functional significance of ezrin-EGFR interaction in non-small cell lung cancer (NSCLC) cells. Endogenous ezrin and EGRF interaction was confirmed by co-immunoprecipitation and immunofluorescent staining. When expression of ezrin was inhibited, EGFR activity and phosphorylation levels of downstream signaling pathway proteins ERK and STAT3 were decreased. Cell fractionation experiments revealed that nuclear EGFR was significantly diminished in ezrin-knockdown cells. Consequently, mRNA levels of EGFR target genes AURKA, COX-2, cyclin D1, and iNOS were decreased in ezrin-depleted cells. A small molecule inhibitor of ezrin, NSC305787, reduced EGF-induced phosphorylation of EGFR and downstream target proteins, EGFR nuclear translocation, and mRNA levels of nuclear EGFR target genes similar to ezrin suppression. NSC305787 showed synergism with erlotinib in wild-type EGFR-expressing NSCLC cells, whereas no synergy was observed in EGFR-null cells. Phosphorylation of ezrin on Y146 was found as an enhancer of ezrin-EGFR interaction and required for increased proliferation, colony formation, and drug resistance to erlotinib. These findings suggest that ezrin-EGFR interaction augments oncogenic functions of EGFR and that targeting ezrin may provide a potential novel approach to overcome erlotinib resistance in NSCLC cells.

PMID:
26936397
PMCID:
PMC5005263
DOI:
10.1016/j.neo.2016.01.002
[Indexed for MEDLINE]
Free PMC Article

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