PHORBOL ESTER AND CYCLIC AMP-MEDIATED REGULATION OF THE MELANOMA-ASSOCIATED CELL-ADHESION MOLECULE MUC18 MCAM/

MUC18/MCAM is a melanoma-associated cell adhesion molecule that is als o occasionally found on carcinomas and other tumor types, On melanomas , MUC18 expression increases with tumor progression and is found on mo re than 70% of metastatic lesions, To investigate the regulation of MU C18 expression, cell lines of diverse tissue origin were exposed to cy tokines, regulators of intracellular cyclic AMP (cAMP), and to phorbol ester, MUC18 expression could not be induced in negative cell lines a nd could only be modulated by changes in cAMP levels or by exposure to phorbol ester in positive cells. An increase in intracellular cAMP le d to an up-regulation in cell surface MUC18 that was maximal at 48 h, Increased MUC18 mRNA levels were observed as soon as 4 h and were 3-fo ld higher than in control cells by 48 h, Exposure of the cells to phor bol ester reduced MUC18 surface expression to background levels by 24 h, This downregulation was associated with decreased mRNA levels that were apparent at 8 h, By 24 h, steady-state levels of MUC18 mRNA had b een reduced by 58%. Whereas similar changes in MUC18 surface expressio n were observed in MUC18-expressing glioma and carcinoma cell lines, m elanoma cells were more resistant to the MUC18-modulating effects of c AMP analogues and phorbol ester, These observations suggest that the s trong MUC18 expression observed in advanced melanomas may reflect dist urbances in the normal regulation of this molecule.