The PI 3-kinase/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factors NF-kappaB and c-Myc in pancreatic cancer cells

Oncogene. 2004 Nov 11;23(53):8571-80. doi: 10.1038/sj.onc.1207902.

Abstract

The persistent activation of signaling cascades results in dramatic consequences that include loss of cellular growth control and neoplastic transformation. We show here that phosphoinositide 3-kinase (PI 3-kinase) and its mediator Akt were constitutively activated in pancreatic cancer and that this might be due to the aberrant expression of their natural antagonist MMAC/PTEN. Indeed, our results show that MMAC/PTEN expression was either lost or significantly reduced in five of eight cell lines and in twelve of seventeen tumor specimens examined. That the poor expression of MMAC/PTEN in pancreatic cancer cells could be due to promoter methylation was indicated by methylation-specific PCR analysis. Our studies also indicated that PI 3-kinase targeted two important transcription factors in pancreatic cancer cells. The ability of constitutively activated NF-kappaB to induce gene expression and the stabilization of c-MYC protein by decreased phosphorylation of Thr58 were both dependent on PI 3-kinase activity. When pancreatic cancer cells were treated with a peptide antagonist of NF-kappaB nuclear translocation, or stably transfected with a dominant-negative mutant of MYC, their proliferation was markedly inhibited. Taken together, these data indicate that the aberrant expression of MMAC/PTEN contributes to the activation of the PI 3-kinase/Akt pathway and its transcription factor mediators in pancreatic cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Cell Line, Tumor
  • Cell Proliferation
  • Humans
  • NF-kappa B / metabolism*
  • PTEN Phosphohydrolase
  • Pancreatic Neoplasms / genetics
  • Pancreatic Neoplasms / metabolism*
  • Pancreatic Neoplasms / pathology
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoric Monoester Hydrolases / antagonists & inhibitors
  • Phosphoric Monoester Hydrolases / genetics
  • Phosphoric Monoester Hydrolases / metabolism*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases / metabolism*
  • Proto-Oncogene Proteins / metabolism*
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-myc / antagonists & inhibitors
  • Proto-Oncogene Proteins c-myc / metabolism*
  • Signal Transduction*
  • Threonine / genetics
  • Threonine / metabolism
  • Tumor Suppressor Proteins / antagonists & inhibitors
  • Tumor Suppressor Proteins / genetics
  • Tumor Suppressor Proteins / metabolism*

Substances

  • NF-kappa B
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-myc
  • Tumor Suppressor Proteins
  • Threonine
  • Phosphatidylinositol 3-Kinases
  • AKT1 protein, human
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins c-akt
  • Phosphoric Monoester Hydrolases
  • PTEN Phosphohydrolase
  • PTEN protein, human