Modulation of ICAM-1 expression by α-MSH in human melanoma cells and melanocytes

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.

TNF-α increases human melanoma cell invasion and migration in vitro: the role of proteolytic enzymes

“…In practice, we found that TNF-a at a concentration of around 100 -250 U ml À1 added for 20 -24 h produced maximal effects on both cell migration and cell invasion. This result is consistent with previous reports from Professor Ghanem's laboratory that stimulation of HBL cells with TNF-a for 24 h resulted in a maximal increase in the expression of ICAM-1 (Morandini et al, 1998). Furthermore, previous work from our group on the effects of TNF-a on two human cutaneous TNF--200 U ml −1 TNF-200 U ml −1 + 2 macroglobulin 2 U ml −1 Figure 4 (A) Effect of the general protease inhibitor a 2 macroglobulin at a concentration of 2 U ml À1 on HBL melanoma cell invasion through fibronectin.…”

Anti-inflammatory and anti-invasive effects of α-melanocyte-stimulating hormone in human melanoma cells

“…These results suggest that a-MSH can effectively reduce cytokineinduced upregulation of adhesion molecules such as integrins that would tend to increase melanoma invasiveness through ECM proteins while also reducing expression of adhesion molecules that promote interaction between melanoma cells and the immune system (e.g. ICAM-1 as we previously demonstrated (Hedley et al, 1998b;Morandini et al, 1998)), thus enhancing melanoma escape of immune surveillance.…”

“…Our group has showed that a-MSH can inhibit tumour necrosis factor-a (TNF-a)-induced upregulation of intercellular adhesion molecule-1 (ICAM-1) in human melanocytes and melanoma cells (Hedley et al, 1998b;Morandini et al, 1998) and reduce interactions between cytokine-stimulated melanoma cells and T lymphocytes . The expression of inflammatory cytokines and adhesion receptors such as ICAM-1 are largely under the control of the transcription factor NF-kB (Ghosh et al, 1998).…”

Human melanocortin 1 receptor (MC1R) gene variants alter melanoma cell growth and adhesion to extracellular matrix

“…However, the response to forskolin, an adenylyl cyclase agonist, in the proliferation and cell adhesion assays by all of the transfected and untransfected cell lines demonstrates that these responses occurred via cAMP production, and that each of the variant MC1R transfectants were capable of responding in a similar manner to the wild type transfectants when the compromised signalling via the variant MC1 receptor was circumvented. Although previous research has shown that aMSH can suppress NF-kB activation and ICAM-1 expression on melanocytes/melanoma cells (Thody et al, 1993;Murata et al, 1997;Morandini et al, 1998;Haycock et al, 1999), we have found that the B16G4F cells (untransfected and MC1R transfected) do not express ICAM-1 constitutively or following addition of TNFa, and fail to increase NF-kB activation following TNFa (data not shown), thereby limiting the usefulness of this cell line in investigating aMSH/MC1R variant induced effects on these parameters.…”

“…Because MC1R is expressed by melanoma cells, it is likely that the aMSH released by the tumour cells has autocrine activity on the melanoma cells, as well as effects on other cell types, including monocytes/ macrophages and lymphocytes, which also express melanocortin receptors (Luger et al, 2000;AbdelMalek, 2001;Neumann et al, 2001). Previous research has demonstrated that aMSH is capable of producing various effects on melanocytes and melanoma cells, for example, suppression of tumour necrosis factor alpha (TNFa) induced intercellular adhesion molecule-1 (ICAM-1) expression, and alterations in binding to extracellular matrix proteins, including fibronectin and laminin (Thody et al, 1993;Murata et al, 1997;Morandini et al, 1998;Hedley et al, 1998;Haycock et al, 1999). It is therefore possible the MC1R variants could have effects on these non-pigmentary pathways, and thereby alter the biological behaviour of melanocytes/melanoma cells during melanoma development and progression.…”