Neural cell adhesion molecule potentiates invasion and metastasis of melanoma cells through CAMP-dependent protein kinase and phosphatidylinositol 3-kinase pathways

Int J Biochem Cell Biol. 2011 Apr;43(4):682-90. doi: 10.1016/j.biocel.2011.01.016. Epub 2011 Jan 26.

Abstract

Neural cell adhesion molecule (NCAM) has been implicated in tumor metastasis yet its function in melanoma progression remains unclear. Here, we demonstrate that stably silencing NCAM expression in mouse melanoma B16F0 cells perturbs their cellular invasion and metastatic dissemination in vivo. The pro-invasive function of NCAM is exerted via dual mechanisms involving both cAMP-dependent protein kinase (PKA) and phosphatidylinositol 3-kinase (PI3K) pathways. Pharmacologic inhibition of PKA and PI3K leads to impaired cellular invasion. In contrast, forced expression of constitutively activated Akt, the major downstream target of PI3K, restores the defective cellular invasiveness of NCAM knock-down (KD) B16F0 cells. Furthermore, attenuation of either PKA or Akt activity in NCAM KD cells is shown to affect their common downstream target, transcription factor cAMP response element binding protein (CREB), which in turn down-regulates mRNA expression of matrix metalloproteinase-2 (MMP-2), thus contributes to impaired cellular invasion and metastasis of melanoma cells. Together, these findings indicate that NCAM potentiates cellular invasion and metastasis of melanoma cells through stimulation of PKA and PI3K signaling pathways thus suggesting the potential implication of anti-NCAM strategy in melanoma treatment.

MeSH terms

  • Animals
  • Cell Line, Tumor
  • Cell Movement
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclic AMP-Dependent Protein Kinases / metabolism*
  • Disease Progression
  • Down-Regulation
  • Enzyme Activation
  • Gene Expression Regulation, Neoplastic
  • Gene Knockdown Techniques
  • Gene Silencing
  • Matrix Metalloproteinase 2 / genetics
  • Melanoma, Experimental / genetics
  • Melanoma, Experimental / pathology*
  • Mice
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Neural Cell Adhesion Molecules / deficiency
  • Neural Cell Adhesion Molecules / genetics
  • Neural Cell Adhesion Molecules / metabolism*
  • Phosphatidylinositol 3-Kinase / metabolism*
  • Phosphorylation
  • Signal Transduction*

Substances

  • Cyclic AMP Response Element-Binding Protein
  • Neural Cell Adhesion Molecules
  • Phosphatidylinositol 3-Kinase
  • Cyclic AMP-Dependent Protein Kinases
  • Matrix Metalloproteinase 2