RESISTANCE OF MELANOMA CELL-LINES TO INTERFERONS CORRELATES WITH REDUCTION OF IFN-INDUCED TYROSINE PHOSPHORYLATION - INDUCTION OF THE ANTIVIRAL STATE BY IFN IS PREVENTED BY TYROSINE KINASE INHIBITORS

Clinical and experimental studies examining the action of IFNs on huma n malignant melanomas and melanoma cell lines have shown that this can cer cell type is frequently IFN resistant. In the present study, the I FN responsiveness of five melanoma cell lines, SK-MEL-28, SK-MEL-3, MM 96, HT-144, and Hs 294T, as determined by the levels of IFN-induced ex pression of the antiviral proteins, 100 kDa 2',5'-oligoadenylate synth etase (OAS) and Mx Ag, was shown to correlate with the IFN responsiven ess of the five lines measured in antiproliferative and antiviral assa ys. Three of the lines, SK-MEL-28 (IFN sensitive), SK-MEL-3 (moderatel y IFN sensitive), and MM96 (IFN insensitive) were analyzed further to ascertain their relative levels of IFN-activated signal transduction. Pretreatment of the three melanoma cell lines with the tyrosine kinase inhibitors, Herbimycin A or Genistein, produced a dose-dependent inhi bition of the antiviral action of IFN-alpha, -beta, and -gamma and the induction of OAS by IFN-beta. Thus, induction of the antiviral state in melanoma cells by IFN requires activation of tyrosine kinase-depend ent signaling pathways. Furthermore, the IFN responsiveness of three m elanoma cell lines could be correlated with the ability to detect by i mmunoblotting of SDS-PAGE displays of cell lysates, IFN-induced tyrosi ne phosphorylated cellular proteins in the range m.w. 80 to 130 kDa. T his induction was also sensitive to the tyrosine kinase inhibitors Her bimycin A and Genistein. Based on these results, we propose that the I FN-resistant melanoma cell lines examined contain a deficiency early i n the IFN signal transduction pathway resulting in a reduced potential for IFN-induced tyrosine phosphorylation and a lack of responsiveness to IFN.