HOMOLOGOUS AND HETEROLOGOUS REGULATION OF ALPHA-MELANOCYTE-STIMULATING HORMONE RECEPTORS IN HUMAN AND MOUSE MELANOMA CELL-LINES

Specific high-affinity receptors for cu-melanocyte-stimulating hormone (alpha-MSH) are found in variable abundance on many melanoma cell lin es. We have examined melanocortin peptides and other factors for their ability to regulate the number of MSH receptors in eleven human and t wo mouse melanoma cell lines. MSH induced up-regulation of its own rec eptors in three human cell lines and down-regulation in six human and two mouse melanoma cell lines. No regulation was observed in two human lines. Scatchard analysis revealed modulation of the number of recept ors per cell without any change in affinity. The concentrations induci ng half-maximal response for up- and down-regulation were 1.6 nM and 0 .23 nM, respectively. ACTH(1-17) and [Nle(4),D-Phe(7)]-alpha-MSH were more potent, whereas ACTH(1-24) desacetyl-alpha-MSH, and [Nle(4)]-alph a-MSH were less potent in receptor up-regulation as compared to alpha- MSH. Down-regulation but not up-regulation could be fully mimicked by G(s)-protein activation and partially by elevation of cellular cAMP. C ombination of different agents which increase cAMP was found to be cou nterregulatory. TPA and retinoic acid generally down-regulated MSH rec eptors but had no effect on HBL cells. Several protein kinase inhibito rs increased MSH binding in B16 cells. MSH-induced receptor down-regul ation and melanin synthesis were most effectively antagonized by selec tive inhibitors of cAMP-dependent protein kinase in these cells. Taken together, MSH receptors on melanoma cells are both positively and neg atively regulated. Whereas cAMP dependent protein kinase activation se ems to be involved in down-regulation, the mechanism responsible for u p-regulation remains to be elucidated.