Functional status and relationships of melanocortin 1 receptor signaling to the cAMP and extracellular signal-regulated protein kinases 1 and 2 pathways in human melanoma cells

Melanocortin-1 receptor (MC1R) is a molecular target for melanoma imaging and therapy because of its overexpression on rodent and human melanoma cells. Here, we evaluated the MC1R targeting and specificity of68Ga-DOTA-GGNle-CycMSHhexand Cy5.5-GGNle-CycMSHhexusing murine and human melanoma cells, and murine and xenografted tumors.68Ga-DOTA-GGNle-CycMSHhexwas used first in human as an imaging probe to evaluate the possibility of radionuclide therapy in patients with advanced-stage melanoma.68Ga-DOTA-GGNle-CycMSHhexand Cy5.5-GGNle-CycMSHhexdisplayed MC1R-specific targeting properties in murine and human melanoma cells, as well as in murine melanoma and human melanoma–xenografted tumors. Both B16/F10 and M21 melanoma lesions could be easily imaged by positron emission tomography using68Ga-DOTA-GGNle-CycMSHhex. The first-in-human images of melanoma brain metastases in patients demonstrated the clinical relevance of MC1R as a molecular target for melanoma imaging, highlighting the potential of68Ga-DOTA-GGNle-CycMSHhexas an MC1R-targeting melanoma imaging probe and underscoring the need to develop MC1R-targeting therapeutic agents for treating patients with metastatic melanoma.

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Contribution of extracellular signal-regulated kinases to the IL-1-induced growth inhibition of human melanoma cells A375

International Immunopharmacology ◽

10.1016/j.intimp.2007.10.013 ◽

2008 ◽

Vol 8 (1) ◽

pp. 80-89 ◽

Cited By ~ 3

Author(s):

Tomohiro Arakawa ◽

Takanori Yamamura ◽

Takayuki Hattori ◽

Hidetoshi Hayashi ◽

Akiko Mori ◽

...

Keyword(s):

Growth Inhibition ◽

Melanoma Cells ◽

Human Melanoma ◽

Human Melanoma Cells ◽

Extracellular Signal

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A3Adenosine Receptor Activation Inhibits Cell Proliferation via Phosphatidylinositol 3-Kinase/Akt-dependent Inhibition of the Extracellular Signal-regulated Kinase 1/2 Phosphorylation in A375 Human Melanoma Cells

Journal of Biological Chemistry ◽

10.1074/jbc.m413772200 ◽

2005 ◽

Vol 280 (20) ◽

pp. 19516-19526 ◽

Cited By ~ 90

Author(s):

Stefania Merighi ◽

Annalisa Benini ◽

Prisco Mirandola ◽

Stefania Gessi ◽

Katia Varani ◽

...

Keyword(s):

Cell Proliferation ◽

Receptor Activation ◽

Melanoma Cells ◽

Human Melanoma ◽

Phosphatidylinositol 3 Kinase ◽

Extracellular Signal Regulated Kinase ◽

Human Melanoma Cells ◽

Extracellular Signal ◽

Dependent Inhibition ◽

Phosphatidylinositol 3

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Mitogen-activated protein kinases control p27/Kip1 expression and growth of human melanoma cells

Biochemical Journal ◽

10.1042/0264-6021:3570297 ◽

2001 ◽

Vol 357 (1) ◽

pp. 297 ◽

Cited By ~ 26

Author(s):

Marcin KORTYLEWSKI ◽

Peter C. HEINRICH ◽

Maria-Elisabeth KAUFFMANN ◽

Markus BÖHM ◽

Andrzej MACKIEWICZ ◽

...

Keyword(s):

Protein Kinases ◽

Melanoma Cells ◽

Human Melanoma ◽

Mitogen Activated Protein Kinases ◽

Human Melanoma Cells ◽

Mitogen Activated Protein ◽

P27 Kip1

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Mitogen-activated protein kinases control p27/Kip1 expression and growth of human melanoma cells

Biochemical Journal ◽

10.1042/bj3570297 ◽

2001 ◽

Vol 357 (1) ◽

pp. 297-303 ◽

Cited By ~ 33

Author(s):

Marcin KORTYLEWSKI ◽

Peter C. HEINRICH ◽

Maria-Elisabeth KAUFFMANN ◽

Markus BÖHM ◽

Andrzej MACKIEWICZ ◽

...

Keyword(s):

Cell Growth ◽

Protein Kinases ◽

Melanoma Cells ◽

Human Melanoma ◽

Mitogen Activated Protein Kinases ◽

Mapk Activity ◽

Human Melanoma Cells ◽

Mitogen Activated Protein ◽

P27 Kip1 ◽

Constitutively Active

The mitogen-activated protein kinases (MAPKs) extracellular signal-regulated protein kinase (ERK)1 and ERK2, involved in regulating cell growth and differentiation, are constitutively active in A375 and WM239 human melanoma cells. Using PD098059, an inhibitor of MAPK kinase (MEK), we investigated the role of persistently activated ERK1/2 in cell growth. The inhibition of MAPK activity induced a dose-dependent growth arrest in G0/G1 phase. Correspondingly, we observed the up-regulation of the cyclin-dependent kinase (Cdk) inhibitor p27/Kip1 and hypophosphorylation of the retinoblastoma protein. Further studies showed that PD098059 treatment significantly decreased Cdk2 kinase activity, most probably owing to an augmented level of p27/Kip1 associated with cyclin E–Cdk2 complexes. The accumulation of p27/Kip1 protein in A375 cells was attributed to its increased stability. Our findings suggest that constitutively active ERK1/2 kinases contribute to the growth of melanoma cells by negative regulation of the p27/Kip1 inhibitor.

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