MSH receptor expression and the relationship to melanogenesis and metastatic activity in B16 melanoma.
In this study we have compared the effects of different pro-opiomelanocortin (POMC) peptides on melanogenesis and metastasis and their relationship to MSH receptor expression in B16F1 melanoma cells. All peptides, apart from beta-endorphin, increased melanogenesis and the order of potency was Nle4DPhe7-alpha-MSH greater than alpha-MSH greater than ACTH[1-39] greater than des-acetyl alpha-MSH greater than ACTH[1-24]. A similar order of potency was found for metastasis, except for ACTH [1-24], which had a relatively greater effect on metastasis. These findings suggest that the effects on melanogenesis and metastasis are mediated via the same receptor. The results of ligand binding studies also indicated the presence of a single receptor with a KD value for Nle4DPhe7-alpha-MSH of 62 +/- 16pM. This was consistent with crosslinking studies using [125I] Nle4DPhe7-alpha-MSH which produced a single 50-55 kD band on analysis by SDS-PAGE. However, the relative binding affinities of the different peptides, measured by displacement of [125I]-Nle4DPhe7-alpha-MSH, did not closely correlate with the relative potencies in stimulating melanogenesis and metastasis. This suggests that receptor activation and the subsequent biological response is not determined solely by binding affinity.
Lunec
J
J
Cancer Research Unit, University of Newcastle upon Tyne Medical School, UK.
Pieron
C
C
Thody
A J
AJ
D000324:Adrenocorticotropic Hormone / Q000494:pharmacology; D000818:Animals; D003366:Cosyntropin / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D008543:Melanins / Q000096:biosynthesis*; D008546:Melanoma, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D009368:Neoplasm Transplantation; D010446:Peptide Fragments / Q000494:pharmacology; D011485:Protein Binding; D011979:Receptors, Pituitary Hormone / Q000096:biosynthesis* / Q000502:physiology; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation; D000521:alpha-MSH / Q000031:analogs & derivatives / Q000494:pharmacology
D008543:Melanins; D009363:Neoplasm Proteins; D010446:Peptide Fragments; D011979:Receptors, Pituitary Hormone; D003366:Cosyntropin; D000521:alpha-MSH; C027756:MSH, 4-Nle-7-Phe-alpha-; C029446:MSH receptor; D000324:Adrenocorticotropic Hormone