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Interferon and Retinoic Acid Suppress the Growth of Human Papillomavirus Type 16 Immortalized Cervical Epithelial Cells, but Only Interferon Suppresses the Level of the Human Papillomavirus Transforming Oncogenes¹

Departments of Physiology and Biophys [C. A., J. R. H., E. A. R., R. L. E.], Environmental Health Sciences [E. A. R.], Reproductive Biology [E. A. R., R. L. E.], Dermatology [R. L. E.], and Biochemistry [J. R. H., R. L. E.], Case Western Reserve University School of Medicine, Cleveland, Ohio 44106

In the present study, we examine the effects of all-trans-retinoic acid (RA) and interferons- and - (IFN- and IFN-) on the growth of HPV16-immortalized cell lines, ECE16-1 and CaSki. Treating proliferating ECE16-1 cells with RA causes a concentration-dependent decrease in cell number. At 1 µM RA, cell growth is suppressed by 65% and the level of mRNA encoding cytokeratin K5, a biochemical marker of retinoid action, is also suppressed. In contrast, the level of transcript encoding the HPV16 oncogenes, E6 and E7, is reduced by only 5 to 10%. IFN- at 1000 IU/ml or IFN- at 200 IU/ml suppresses growth by 70%. This growth suppression by IFN- is correlated with a >90% reduction in E6/E7 mRNA levels. Additional growth suppression is observed upon simultaneous treatment with retinoid and interferon. Optimal suppression is observed in the presence of 200 IU/ml IFN- and 1 µM RA. The rank order of effectiveness is IFN-/RA > IFN-/RA = IFN- > RA > IFN-. In contrast to the suppression of ECE16-1 cell growth, RA causes a concentration-dependent increase in CaSki cell number (50–60%) which is optimal at 1 µM RA. Cytokeratin K5 mRNA levels are markedly suppressed, and E6/E7 mRNA levels increased by 5% under these conditions. IFN- at 1000 IU/ml or IFN- at 200 IU/ml decreases CaSki cell growth by 20 and 45%, respectively, and 200 IU/ml of IFN- reduce E6/E7 expression to undetectable levels. Addition of RA (1 µM) partially counters the IFN-dependent suppression of growth and E6/E7 mRNA levels. Our results suggest that retinoid-dependent changes in human papillomavirus-immortalized cervical cell proliferation are not always correlated with changes in E6/E7 transcript levels.

¹ This work was supported by a grant from the American Institute for Cancer Research (R. L. E.) and utilized the facilities of the Skin Diseases Research Center of Northeast Ohio (NIH, AR39750). J. R. H. was supported by the Metabolism Training Program (NIH, DK07319).

² To whom requests for reprints should be addressed, at Department of Physiology and Biophysics, Room E532, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4970.

Received 7/ 2/93. Accepted 2/15/94.

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