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

Oncogene volume 23, pages 8571–8580 (2004)Cite this article

An Erratum to this article was published on 16 June 2005

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-κB 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-κB 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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Acknowledgements

We gratefully acknowledge Drs Peter Sabbatini, Boudewijn Burgering and Dimpy Koul for the Akt constructs used in this study, Drs Robert N Eisenman, René Bernards, Masato Kasuga and Anke Klippel for M4-luciferase reporter, pCMV-MADMYC, p85DN and p110KR, respectively. We also thank Drs Michael A Davies and Dimpy Koul for their assistance with the viral infection experiments, Drs Paul Chiao and Douglas Evans for the pancreatic adenocarcinoma specimens and Walter Pagel for reading the manuscript. This work was supported by a grant (to SAR) from the Lustgarten Foundation for Pancreatic Cancer Research and by funds from the University Cancer Foundation (to SAR) at the University of Texas MD Anderson Cancer Center. We received valuable assistance from the DNA sequencing and Media preparation facilities at the University of Texas MD Anderson Cancer Center, which are supported by a grant from the National Cancer Institute (CA016672).

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  1. Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, 77030, TX, USA

    Takayuki Asano, Yixin Yao, Jijiang Zhu, Donghui Li, James L Abbruzzese & Shrikanth A G Reddy

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  1. Takayuki Asano
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  2. Yixin Yao
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Correspondence to Shrikanth A G Reddy.

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Asano, T., Yao, Y., Zhu, J. et al. The PI 3-kinase/Akt signaling pathway is activated due to aberrant Pten expression and targets transcription factors NF-κB and c-Myc in pancreatic cancer cells. Oncogene 23, 8571–8580 (2004). https://doi.org/10.1038/sj.onc.1207902

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