Regulation of c-met expression in B16 murine melanoma cells by melanocyte stimulating hormone.
B16 murine melanoma cells selected in vivo for enhanced liver metastatic ability (B16-LS9) show on the one hand an increased expression and constitutive activation of the proto-oncogene c-met (the receptor for hepatocyte growth factor/scatter factor), and on the other hand a more differentiated phenotype, when compared to the parental cell line, B16-F1. Following this observation, we have tried to establish whether there is a direct relationship between differentiation and c-met expression in B16 melanoma cells. Treatment of these cells with differentiating agents indicated that c-met expression was strongly induced by melanocyte stimulating hormone, while retinoic acid had almost no influence. c-met induction was triggered by engagement of the melanocortin receptor, cAMP elevation and PKA/PKC(&agr;) activation, as respectively shown by the effects of ACTH, cAMP elevating agents and specific PK inhibitors. Regulation of c-met expression via the melanocortin receptor and cAMP raises the intriguing possibility that autocrine and/or paracrine mechanisms acting in vivo on this circuit might influence (through c-met expression and activation) the metastatic behavior of these tumor cells, which we have shown to be dependent on their c-met expression.
Rusciano
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Friedrich Miescher Institute, PO Box 2543, CH-4002 Basel, Switzerland. rusciano@fmi.ch.
Lorenzoni
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Burger
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D000818:Animals; D002454:Cell Differentiation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D007527:Isoenzymes / Q000378:metabolism; D009074:Melanocyte-Stimulating Hormones / Q000494:pharmacology*; D008546:Melanoma, Experimental / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011493:Protein Kinase C / Q000378:metabolism; D051571:Protein Kinase C-alpha; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D011519:Proto-Oncogenes / Q000187:drug effects*; D018043:Receptors, Corticotropin / Q000378:metabolism; D044101:Receptors, Melanocortin; D014212:Tretinoin / Q000494:pharmacology; D014407:Tumor Cells, Cultured