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Modulation of ICAM-1 expression by alpha-MSH in human melanoma cells and melanocytes
R Morandini1, J M Boeynaems, S J Hedley
1LOCE, Institut J. Bordet-ULB, Faculté de Médecine, Bruxelles, Belgium. rmorand@resulb.ulb.ac.be
Abstract:
Alpha-MSH, a proopiomelanocortin (POMC)-derived peptide, is known to be produced in the pituitary, the skin, and melanoma tumors and to possess many biological effects, mainly on melanocyte pigmentation and growth. Moreover, the melanocyte expresses adhesion molecules, including ICAM-1. The latter has been reported to play a role in melanoma spread and associated metastatic process. We conducted a study in order to evaluate the possible effect of MSH on ICAM-1 expression in human cultured malignant and normal melanocytes. Our data show that alpha-MSH inhibits ICAM-1 expression stimulated by TNF in a concentration-dependent manner, both at the protein and gene expression level. Ninety percent inhibition was obtained with 10 nM MSH, while 50% inhibition was achieved with 1 nM. Endogenous cAMP elevation with forskolin as well as an exogenous cAMP stable analogue (Sp-cAMPS) produced the same inhibitory effect. A screening of malignant melanocytes showed that inhibition of ICAM-1 expression could be achieved only in those cells expressing detectable MSH receptors and seemed to correlate with the number of binding sites. In conclusion, our data strongly suggest alpha-MSH as a potent inhibitor of ICAM-1 expression in malignant melanocytes acting through MSH receptor stimulation and subsequent cAMP increase.
Insights
Alpha-melanocyte-stimulating hormone (alpha-MSH) effectively inhibits Intercellular Adhesion Molecule-1 (ICAM-1) expression in melanoma cells. This inhibition, mediated by MSH receptors and cAMP, suggests a therapeutic role for alpha-MSH in melanoma treatment.
Area of Science:
- Endocrinology
- Dermatology
- Oncology
Background:
- Alpha-melanocyte-stimulating hormone (alpha-MSH), derived from proopiomelanocortin (POMC), influences melanocyte pigmentation and growth.
- Melanocytes express Intercellular Adhesion Molecule-1 (ICAM-1), a molecule implicated in melanoma metastasis.
- The role of alpha-MSH in regulating ICAM-1 expression in melanocytes was previously unexplored.
Purpose of the Study:
- To investigate the effect of alpha-MSH on ICAM-1 expression in cultured human malignant and normal melanocytes.
- To determine the concentration-dependency and mechanism of alpha-MSH's effect on ICAM-1.
Main Methods:
- Cultured human malignant and normal melanocytes were treated with alpha-MSH.
- Tumor Necrosis Factor (TNF) was used to stimulate ICAM-1 expression.
- Protein and gene expression levels of ICAM-1 were analyzed.
- Intracellular cyclic AMP (cAMP) levels were modulated using forskolin and Sp-cAMPS.
- MSH receptor expression and binding capacity were assessed in malignant melanocytes.
Main Results:
- Alpha-MSH significantly inhibited TNF-stimulated ICAM-1 expression in a concentration-dependent manner at both protein and gene levels.
- Approximately 90% inhibition was observed at 10 nM alpha-MSH, with 50% inhibition at 1 nM.
- Elevation of intracellular cAMP levels mimicked the inhibitory effect of alpha-MSH.
- Inhibition of ICAM-1 expression was observed only in malignant melanocytes expressing detectable MSH receptors, correlating with binding site density.
Conclusions:
- Alpha-MSH acts as a potent inhibitor of ICAM-1 expression in malignant melanocytes.
- The mechanism involves MSH receptor stimulation leading to increased intracellular cAMP.
- These findings suggest alpha-MSH as a potential therapeutic agent for managing melanoma spread by downregulating ICAM-1.