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Regulation of iNOS by the p44/42 mitogen-activated protein kinase pathway in human melanoma

J A Ellerhorst1, S Ekmekcioglu, M K Johnson

  • 1The Department of Experimental Therapeutics, The University of Texas, MD Anderson Cancer Center, Houston, 77030, USA. jaellerh@mdanderson.org

Oncogene
|February 14, 2006
PubMed

Insights

Activating mutations in NRAS and BRAF genes drive inducible nitric oxide synthase (iNOS) expression in melanoma. This pathway contributes to poor patient survival, highlighting iNOS as a potential therapeutic target.

Area of Science:

  • Molecular Biology
  • Oncology
  • Biochemistry

Background:

  • Activating mutations in NRAS and BRAF genes are frequent in melanoma and activate the p44/42 mitogen-activated protein kinase (MAPK) pathway.
  • The p44/42 MAPK pathway has been implicated in the regulation of inducible nitric oxide synthase (iNOS) gene expression in non-melanoma cell systems.
  • Melanoma iNOS expression is associated with shortened patient survival.

Purpose of the Study:

  • To investigate the hypothesis that activating NRAS or BRAF mutations drive iNOS expression in human melanoma via the p44/42 MAPK pathway.
  • To confirm the role of iNOS activity in melanoma cell proliferation.
  • To examine the association between NRAS/BRAF mutations, MAPK pathway activation, and iNOS expression in human melanoma tissue.

Main Methods:

  • Inhibition of iNOS activity using S-methylisothiourea.
  • Inhibition of the p44/42 MAPK pathway using U0126 and BRAF RNA interference.
  • Analysis of 20 human melanoma tumors for NRAS/BRAF mutations, ERK phosphorylation (a marker of MAPK pathway activation), and iNOS expression.

Main Results:

  • Inhibition of iNOS activity decreased melanoma cell proliferation.
  • The p44/42 MAPK pathway was demonstrated to regulate iNOS expression in melanoma cells.
  • A significant association was found between NRAS/BRAF mutations, ERK phosphorylation, and iNOS expression in human melanoma tumors.

Conclusions:

  • Activating mutations in NRAS and BRAF drive constitutive iNOS expression in human melanoma.
  • This pathway contributes to nitric oxide production and is associated with poor patient survival.
  • iNOS represents a potential therapeutic target in melanoma.

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