Interferon regulates expression of mda-6/WAF1/CIP1 and cyclin-dependent kinases independently from p53 in B16 murine melanoma cells

Interferons (IFNs) induce growth arrest and terminal differentiation through regulation of proliferative genes in a variety of cell types including tumor cells, Growth of melanoma cells is believed to be controlled by the cyclin-dependent kinase inhibitor, mda-6/WAF1/CIP1 gene, IFNs affect the expression of WAF1 in several cell types, including human melanomas. In our earlier reports we demonstrated the antitumor and anticellular activities of different IPN-types on B16 murine melanoma cells. The present study aimed to demonstrate the involvement of mda-6/WAF1 and related cyclin-dependent kinases in antitumor action of different IFN-types in B16 melanoma cells. IFN-alpha has been proven to be a potent inducer of mda-6/WAF1, also inhibiting cyclin-dependent kinases, such as cdc2- and cdk2-kinase. This induction is p53-independent. However, IFN-gamma affects B16 cells differently, it induces p53 activity without inducing WAF1. The combination of IFN-alpha plus IFN-gamma is additive rather than synergistic. Our data demonstrate differential effects of different IFNs on murine B16 melanoma cells which may have relevance in nonsurgical treatment of melanomas. (C) 1997 Academic Press.