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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.

Publication ,  Journal Article
Asano, T; Yao, Y; Zhu, J; Li, D; Abbruzzese, JL; Reddy, SAG
Published in: Oncogene
November 11, 2004

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.

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Published In

Oncogene

DOI

ISSN

0950-9232

Publication Date

November 11, 2004

Volume

23

Issue

53

Start / End Page

8571 / 8580

Location

England

Related Subject Headings

  • Tumor Suppressor Proteins
  • Threonine
  • Signal Transduction
  • Proto-Oncogene Proteins c-myc
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins
  • Protein Serine-Threonine Kinases
  • Phosphorylation
  • Phosphoric Monoester Hydrolases
  • Phosphatidylinositol 3-Kinases
 

Citation

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Asano, T., Yao, Y., Zhu, J., Li, D., Abbruzzese, J. L., & Reddy, S. A. G. (2004). 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, 23(53), 8571–8580. https://doi.org/10.1038/sj.onc.1207902
Asano, Takayuki, Yixin Yao, Jijiang Zhu, Donghui Li, James L. Abbruzzese, and Shrikanth A. G. Reddy. “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 23, no. 53 (November 11, 2004): 8571–80. https://doi.org/10.1038/sj.onc.1207902.
Asano, Takayuki, et al. “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, vol. 23, no. 53, Nov. 2004, pp. 8571–80. Pubmed, doi:10.1038/sj.onc.1207902.

Published In

Oncogene

DOI

ISSN

0950-9232

Publication Date

November 11, 2004

Volume

23

Issue

53

Start / End Page

8571 / 8580

Location

England

Related Subject Headings

  • Tumor Suppressor Proteins
  • Threonine
  • Signal Transduction
  • Proto-Oncogene Proteins c-myc
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins
  • Protein Serine-Threonine Kinases
  • Phosphorylation
  • Phosphoric Monoester Hydrolases
  • Phosphatidylinositol 3-Kinases