IFITM3 as a Potential Mechanism for Cyr61 Mediated Inhibition of Oncolytic Virotherapy
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Publisher:The Ohio State University
Series/Report no.:The Ohio State University. School of Biomedical Sciences Honors Theses; 2011
Oncolytic virus therapy (OV therapy) exploits naturally occurring or genetically modified viruses to kill cancer cells by lytic destruction. Cysteine-rich protein 61 (Cyr61) has been found to be upregulated by OV infection. Cyr61 was found to inhibit OV infection when using a transient transfection model and when using a tetracycline inducible Cyr61 expression model. In vivo studies using the tetracycline inducible cell lines have shown an inhibition of infection with both subcutaneous and intracranial models. Expression was verified in vitro and in vivo using Western blot. Interferon-induced transmembrane protein 3 (IFITM3) was found to be upregulated in the presence of high levels of Cyr61. As IFITM3 has been previously shown to inhibit the influenza A virus, filoviruses, SARS coronavirus and the HIV-1 virus, its upregulation was posited as the potential mechanism for the observed Cyr61 mediated OV inhibition and thus a potential target for the improvement of treatment efficacy. Indeed, IFITM3 protein was found to be upregulated following OV infection by Western blot in several glioma cell lines. In order to test the effect of IFITM3 on infection, U87, Ln229 and U251T2 cells transiently transfected with IFITM3 protein were infected with an oncolytic herpes simplex virus (HSV-1) harboring a luciferase reporter transgene under an immediate early promoter. Viral quantification was performed by quantifying luciferase activity, normalized to GAPDH protein concentration. No inhibition of OV infection upon increased IFITM3 levels was noted in any cell line. Therefore, it was concluded that IFITM3 is unlikely to be a mediator of OV therapy inhibition or a target for treatment efficacy improvement.
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