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Clinical Cancer Research Vol. 5, 2242-2250, August 1999
© 1999 American Association for Cancer Research

Experimental Therapeutics, Preclinical Pharmacology

Adenovirus-mediated E2F-1 Gene Transfer Inhibits MDM2 Expression and Efficiently Induces Apoptosis in MDM2-overexpressing Tumor Cells1

Hai Liang Yang2, Yan Bin Dong2, Mary Jane Elliott, Ta Jen Liu, Cesar Atienza, Jr., Ariel Stilwell and Kelly M. McMasters3

Department of Surgery, James Graham Brown Cancer Center, University of Louisville, Louisville, Kentucky 40202 [H. L. Y., Y. B. D., M. J. E., C. A., A. S., K. M. M.] and the M.D. Anderson Cancer Center, University of Texas, Houston, Texas 77030 [T. J. L.]

The oncoprotein MDM2 binds and inactivates p53. MDM2 also binds to the tumor suppressor pRB, as well as E2F-1. E2F-1 is a transcription factor that regulates S phase entry and has been shown to cause apoptosis in some cell types when overexpressed. To investigate the effect of adenovirus-mediated E2F-1 overexpression, MDM2-overexpressing tumor cell lines were treated by mock infection, infection with an adenoviral vector expressing ß galactosidase, or E2F-1 (Ad5CMV-E2F-1). Western blot analysis confirmed significant overexpression of E2F-1 in Ad5CMV-E2F-1-infected cells. E2F-1 overexpression resulted in marked growth inhibition and rapid loss of cell viability. Ad5CMV-E2F-1 infection resulted in early S phase entry, followed by apoptotic cell death. E2F-1 overexpression was associated with a marked decrease in MDM2 levels and no evidence of increased Bax levels, whereas p53 and Bcl-2 levels remained undetectable. Cleavage of poly-ADP-ribose polymerase and caspase 3/CPP32 implicated activation of the caspase cascade in E2F-1-mediated apoptosis. These results indicate that adenovirus-mediated E2F-1 overexpression in MDM2-overexpressing tumor cells results in decreased MDM2 expression and widespread apoptosis. Because MDM2-overexpressing tumors are often resistant to p53 gene therapy, adenovirus-mediated E2F-1 gene therapy may be a promising alternative strategy.




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Copyright © 1999 by the American Association for Cancer Research.