Transduction of retinoic acid and gamma-interferon signal for intercellular adhesion molecule-1 expression on human tumor cell lines: evidence for the late-acting involvement of protein kinase C inactivation.

Abstract

Intercellular adhesion molecule 1 (ICAM-1) is a major adhesion receptor of the immune system. Its cell surface expression on a wide variety of cells including cancer cells regulated by various proinflammatory cytokines. Incubation of the human glioma cell line HS 683 and the neuroblastoma cell line SK-N-SH with 12-phorbol 13-myristic acid (PMA), retinoic acid, or gamma-interferon (IFN-gamma) strongly stimulates ICAM-1 expression. In the present study, we investigated the role of the protein kinase C (PKC)-mediated signal transduction pathway in this process. We found that IFN-gamma, but not retinoic acid, was able to induce activation and translocation of PKC after 60 min in a dose-dependent fashion, contrasting with the very rapid activation and translocation induced by PMA which occurred at 15 min. The PKC inhibitors 1-(5-isoquinolinesulfonyl)-2-methyl-piperazine dihydrochloride and staurosporine, as well as depletion of PKC by a 24-h treatment with 100 nM PMA, decreased the PMA-mediated stimulation but not the retinoic acid- or the IFN-gamma-mediated stimulation of ICAM-1 expression. On the contrary, they rather stimulated ICAM-1 expression. Furthermore, this stimulation was additive with retinoic acid and IFN-gamma. A 24-h incubation in the presence of retinoic acid or IFN-gamma strongly inhibited activation and translocation of PKC by PMA. These results suggest that although PMA-induced ICAM-1 expression is PKC dependent on HS 683 and SK-N-SH cells, the stimulation of ICAM-1 expression by retinoic acid and by IFN-gamma may be due to PKC inactivation at longer time points (24 h), as mimicked by 1-(5-isoquinolinesulfonyl)-2-methylpiperazine dihydrochloride, staurosporine, or PKC depletion by high doses of PMA.