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J Biol Chem. 2016 Jun 17;291(25):13257-70. doi: 10.1074/jbc.M116.718189. Epub 2016 May 2.

Ezrin Inhibition Up-regulates Stress Response Gene Expression.

Author information

1
From the Departments of Oncology and.
2
From the Departments of Oncology and the Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Bahçeşehir University, 34349 Istanbul, Turkey.
3
the Chemical Biology Laboratory, Center for Cancer Research, NCI, National Institutes of Health, Frederick, Maryland 21702.
4
the Department of Preventive Oncology, Cancer Institute, Hacettepe University, 06800 Ankara, Turkey.
5
the Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University, Washington, D. C. 20057.
6
Pathology, Georgetown University Medical Center, Washington, D. C. 20007.
7
the Department of Pathology, Seirei Mikatahara Hospital and Hamamatsu University School of Medicine, Hamamatsu, Japan, and the Department of Pathology and.
8
the Departments of Oncology and Medicine, Division of Clinical Pharmacology, School of Medicine, and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland 21218.
9
From the Departments of Oncology and au26@georgetown.edu.

Abstract

Ezrin is a member of the ERM (ezrin/radixin/moesin) family of proteins that links cortical cytoskeleton to the plasma membrane. High expression of ezrin correlates with poor prognosis and metastasis in osteosarcoma. In this study, to uncover specific cellular responses evoked by ezrin inhibition that can be used as a specific pharmacodynamic marker(s), we profiled global gene expression in osteosarcoma cells after treatment with small molecule ezrin inhibitors, NSC305787 and NSC668394. We identified and validated several up-regulated integrated stress response genes including PTGS2, ATF3, DDIT3, DDIT4, TRIB3, and ATF4 as novel ezrin-regulated transcripts. Analysis of transcriptional response in skin and peripheral blood mononuclear cells from NSC305787-treated mice compared with a control group revealed that, among those genes, the stress gene DDIT4/REDD1 may be used as a surrogate pharmacodynamic marker of ezrin inhibitor compound activity. In addition, we validated the anti-metastatic effects of NSC305787 in reducing the incidence of lung metastasis in a genetically engineered mouse model of osteosarcoma and evaluated the pharmacokinetics of NSC305787 and NSC668394 in mice. In conclusion, our findings suggest that cytoplasmic ezrin, previously considered a dormant and inactive protein, has important functions in regulating gene expression that may result in down-regulation of stress response genes.

KEYWORDS:

ezrin; gene expression; metastasis; osteosarcoma; small molecule; transgenic mice

PMID:
27137931
PMCID:
PMC4933238
DOI:
10.1074/jbc.M116.718189
[Indexed for MEDLINE]
Free PMC Article

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