title: Ezrin Inhibition Up-regulates Stress Response Gene Expression.
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.
authors.affiliation: From the Departments of Oncology and.
authors.forename: Haydar
authors.initials: H
authors.lastname: Çelik
authors.affiliation: From the Departments of Oncology and the Department of Molecular Biology and Genetics, Faculty of Engineering and Natural Sciences, Bahçeşehir University, 34349 Istanbul, Turkey.
authors.forename: Gülay
authors.initials: G
authors.lastname: Bulut
authors.affiliation: From the Departments of Oncology and.
authors.forename: Jenny
authors.initials: J
authors.lastname: Han
authors.affiliation: From the Departments of Oncology and.
authors.forename: Garrett T
authors.initials: GT
authors.lastname: Graham
authors.affiliation: From the Departments of Oncology and.
authors.forename: Tsion Z
authors.initials: TZ
authors.lastname: Minas
authors.affiliation: From the Departments of Oncology and.
authors.forename: Erin J
authors.initials: EJ
authors.lastname: Conn
authors.affiliation: From the Departments of Oncology and.
authors.forename: Sung-Hyeok
authors.initials: SH
authors.lastname: Hong
authors.affiliation: the Chemical Biology Laboratory, Center for Cancer Research, NCI, National Institutes of Health, Frederick, Maryland 21702.
authors.forename: Gary T
authors.initials: GT
authors.lastname: Pauly
authors.affiliation: the Department of Preventive Oncology, Cancer Institute, Hacettepe University, 06800 Ankara, Turkey.
authors.forename: Mutlu
authors.initials: M
authors.lastname: Hayran
authors.affiliation: the Department of Biostatistics, Bioinformatics, and Biomathematics, Georgetown University, Washington, D. C. 20057.
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.affiliation: Pathology, Georgetown University Medical Center, Washington, D. C. 20007.
authors.forename: Metin
authors.initials: M
authors.lastname: Özdemirli
authors.affiliation: the Department of Pathology, Seirei Mikatahara Hospital and Hamamatsu University School of Medicine, Hamamatsu, Japan, and the Department of Pathology and.
authors.forename: Ayşe
authors.initials: A
authors.lastname: Ayhan
authors.affiliation: 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.
authors.forename: Michelle A
authors.initials: MA
authors.lastname: Rudek
authors.affiliation: From the Departments of Oncology and.
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Toretsky
authors.affiliation: From the Departments of Oncology and au26@georgetown.edu.
authors.forename: Aykut
authors.initials: A
authors.lastname: Üren
mesh_terms: D000218:Adamantane / Q000031:analogs & derivatives / Q000493:pharmacokinetics / Q000494:pharmacology; D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D003598:Cytoskeletal Proteins / Q000037:antagonists & inhibitors*; D004285:Dogs; D005260:Female; D006207:Half-Life; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000556:secondary; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008822:Mice, Transgenic; D012516:Osteosarcoma / Q000188:drug therapy / Q000556:secondary; D010636:Phenols / Q000493:pharmacokinetics / Q000494:pharmacology; D011804:Quinolines / Q000493:pharmacokinetics / Q000494:pharmacology; D015363:Quinolones / Q000493:pharmacokinetics / Q000494:pharmacology; D013312:Stress, Physiological; D059467:Transcriptome; D023041:Xenograft Model Antitumor Assays; D000099149:Ezrin
chemical_list: D000218:Adamantane; D000970:Antineoplastic Agents; D003598:Cytoskeletal Proteins; D010636:Phenols; D011804:Quinolines; D015363:Quinolones; D000099149:Ezrin; C570896:NSC305787; C570897:NSC668394
keywords: ezrin; gene expression; metastasis; osteosarcoma; small molecule; transgenic mice