A selective protein kinase C inhibitor (CGP 41251) positively and negatively modulates melanoma cell MSH receptors.
Melanoma cells express receptors for melanocyte-stimulating hormone (MSH) in variable abundance. CGP 41251, a derivative of staurosporine with an increased selectivity for protein kinase C (PKC) inhibition, was found to modulate MSH receptors in human D10 and HBL cells and in the mouse B16 cell line. Up-regulation was observed in D10 and B16 cells at a concentration of 290 nM and 190 nM, respectively. In HBL cells, however, the PKC inhibitor induced a pronounced MSH receptor down-regulation with an EC50 of only 32 nM. In D10 and HBL cells, alpha-MSH and CGP 41251 synergistically regulated MSH receptors whereas these agents had an antagonistic effect in B16 cells. PKC stimulation by short-term treatment with phorbol ester had an opposite effect on MSH receptors as compared to CGP 41251. In B16 cells, CGP 41251 at a concentration of 100 nM increased the sensitivity to MSH-induced melanogenesis. The staurosporine derivative inhibited proliferation of HBL, B16, and D10 cells at EC50s of 180 nM, 190 nM, and 520 nM, respectively. Furthermore, CGP 41251 increased the dendricity of the cells. In a concentration range between 300 nM and 1 mu M, CGP 41251 induced a sharp increase of the mean cell diameter from 16 mu m to 19 mu m. Thus, the effects of the selective PKC inhibitor on MSH receptors are induced at lower concentrations than needed for the inhibition of proliferation or for the change in cell morphology. These results suggest that the number of MSH receptors expressed on the surface of cultured melanoma cells correlates with the level of constitutive PKC activity in individual cell lines.
Laboratory of Endocrinology, Department of Research, University Hospital, Basel, Switzerland.
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Siegrist
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Sauter
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Eberle
D002455:Cell Division / Q000187:drug effects; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008543:Melanins / Q000096:biosynthesis; D009074:Melanocyte-Stimulating Hormones / Q000378:metabolism / Q000494:pharmacology; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D011979:Receptors, Pituitary Hormone / Q000187:drug effects* / Q000378:metabolism*; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D015854:Up-Regulation
D004791:Enzyme Inhibitors; D008543:Melanins; D011979:Receptors, Pituitary Hormone; C029446:MSH receptor; D009074:Melanocyte-Stimulating Hormones; D011493:Protein Kinase C; D019311:Staurosporine; C059539:midostaurin