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Inhibitors of Epidermal Growth Factor Receptor Kinase and of Cyclin-dependent Kinase 2 Activation Induce Growth Arrest, Differentiation, and Apoptosis of Human Papilloma Virus 16-immortalized Human Keratinocytes¹

Laboratory of Experimental Surgery [H. B-B., Z. H., Z. S., R. L.] and Department of Molecular Biology and Genetic Engineering [S. R-M., R. T.], Hadassah University Hospital, P.O. Box 12000 IL-Q1120 Jerusalem, Israel; Department of Biological Chemistry, Institute of Life Sciences [N. K-D., A. G., A. L.], and Department of Organic Chemistry, Institute of Chemistry [A. G.], The Hebrew University of Jerusalem, Givat Ram, Jerusalem 91904, Israel; and SUGEN, Inc., Redwood City, California 94063 [G. P.]

Human papilloma virus 16 (HPV 16) is associated with cervical cancer and is therefore considered a major health risk for women. Immortalization of keratinocytes induced by HPV infection is largely due to the binding of p53 and Rb by the the viral oncoproteins E6 and E7, respectively, and is driven to a large extent by a transforming growth factor /amphiregulin epidermal growth factor receptor autocrine loop. In this study, we show that the growth of HPV 16-immortalized human keratinocytes can be blocked by a selective epidermal growth factor receptor kinase inhibitor, AG 1478, and by AG 555, a blocker of cyclin-dependent kinase 2 (Cdk2) activation. AG 1478 induces a massive increase in the Cdk2 protein inhibitors p27 and p21, whereas AG 555 appears to have a different mechanism of action, inhibiting the activation of Cdk2. Growth arrest induced by AG 1478 and AG 555 is accompanied by up to 20% of cells undergoing apoptosis. Following AG 1478 treatment but not AG 555 treatment, up to 50% of cells undergo terminal keratinocyte differentiation as determined by filaggrin expression and by the decline in the expression of cytokeratin 14. The growth-arresting properties of AG 1478 and AG 555 identifies them as possible lead antipapilloma agents.

¹ This study was partially supported by the Konover Cancer Fund, The Hebrew University of Jerusalem, and by the FJM Foundation.

² To whom requests for reprints should be addressed. Phone: 972-2-6585404; Fax: 972-2-6512958; E-mail: levitzki@vms.huji.ac.il.

Received 3/28/97. Accepted 6/26/97.

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