Abstract
Activating mutations of the genes for NRAS and BRAF, components of the p44/42 mitogen-activated protein kinase (MAPK) pathway, are common findings in melanoma. Recent evidence in several nonmelanoma cell systems supports the regulation of the inducible nitric oxide synthase (iNOS) gene by this pathway. On the basis of our data showing that melanoma iNOS expression predicts shortened patient survival, we formulated the hypothesis that activating mutations of NRAS or BRAF, which lead to constitutive activation of the p44/42 MAPK pathway, drive iNOS expression in human melanoma. In the present study, we have shown that inhibition of melanoma iNOS activity by S-methylisothiourea leads to decreased cell proliferation, confirming the importance of iNOS activity for melanoma cell growth. Regulation of melanoma iNOS expression by the p44/42 MAPK pathway was demonstrated by inhibition of the pathway by U0126, and by BRAF RNA interference. To explore this regulatory pathway in human tissue, 20 melanoma tumors were examined for NRAS and BRAF mutations, immunohistochemical evidence of ERK phosphorylation, and iNOS expression. A significant association was found among these three features. We conclude that in human melanoma, activating mutations of NRAS and BRAF drive constitutive iNOS expression and, implicitly, nitric oxide production, contributing to the poor survival of these patients.
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Acknowledgements
We thank Erika Thompson, Viju Varghese, Rashmi Pershad, and the staff of the MDACC DNA Analysis Core Facility for expert DNA sequencing; Drs A Hafeez Diwan and Victor Prieto for assistance in interpretation of immunohistochemistry data; and Lihong Long, Anita Myer, Sandra Kinney, Sandra Yekell, and Sandra Ortega-Mendez for technical advice and contributions.
This work was supported by NIH R01 CA90282 (EAG, SE); NIH P50 CA093459 (EAG, SE, JAE); and NIH CA16672 (DNA analysis facility). Its contents are solely the responsibility of the authors and do not necessarily represent the official views of the National Institutes of Health.
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Ellerhorst, J., Ekmekcioglu, S., Johnson, M. et al. Regulation of iNOS by the p44/42 mitogen-activated protein kinase pathway in human melanoma. Oncogene 25, 3956–3962 (2006). https://doi.org/10.1038/sj.onc.1209419
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DOI: https://doi.org/10.1038/sj.onc.1209419
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