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Homologous and Heterologous Regulation of -Melanocyte-stimulating Hormone Receptors in Human and Mouse Melanoma Cell Lines¹

Laboratory of Endocrinology, Department of Research (ZLF), University Hospital and University Children's Hospital, Ch-4031 Basel, Switzerland

Specific high-affinity receptors for -melanocyte-stimulating hormone (-MSH) are found in variable abundance on many melanoma cell lines. We have examined melanocortin peptides and other factors for their ability to regulate the number of MSH receptors in eleven human and two mouse melanoma cell lines. MSH induced up-regulation of its own receptors 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 receptors per cell without any change in affinity. The concentrations inducing half-maximal response for up- and down-regulation were 1.6 nM and 0.23 nM, respectively. ACTH_1–17 and [Nle⁴,D-Phe⁷]--MSH were more potent, whereas ACTH_1–24, desacetyl--MSH, and [Nle⁴]--MSH were less potent in receptor up-regulation as compared to -MSH. Down-regulation but not up-regulation could be fully mimicked by G_s-protein activation and partially by elevation of cellular cAMP. Combination of different agents which increase cAMP was found to be counterregulatory. TPA and retinoic acid generally down-regulated MSH receptors but had no effect on HBL cells. Several protein kinase inhibitors increased MSH binding in B16 cells. MSH-induced receptor down-regulation and melanin synthesis were most effectively antagonized by selective inhibitors of cAMP-dependent protein kinase in these cells. Taken together, MSH receptors on melanoma cells are both positively and negatively regulated. Whereas cAMP-dependent protein kinase activation seems to be involved in down-regulation, the mechanism responsible for up-regulation remains to be elucidated.

¹ Presented in preliminary forms at the 9^th International Congress of Endocrinology, August 30–September 5, 1992, Nice, France, and at the 5^th Swiss Workshop of Methodology in Receptor Research, May 10–14, 1992, Agno-Lugano, Switzerland. This work was supported by the Swiss National Science Foundation (Grant 3100-25653), the Swiss Cancer League, and the Fund of the Department of Research.

² To whom reprint requests should be addressed.

Received 12/ 3/93. Accepted 3/17/94.

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