K-Ras promotes growth transformation and invasion of immortalized human pancreatic cells by raf and phosphatidylinositol 3-kinase signaling

Paul M. Campbell, Angela L. Groehler, Kwang M. Lee, Michel M Ouellette, Vladimir Khazak, Channing J. Der

Research output: Contribution to journalArticle

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Abstract

Mutational activation of the K-Ras oncogene is well established as a key genetic step in the development and growth of pancreatic adenocarcinomas. However, the mechanism by which aberrant Ras signaling promotes uncontrolled pancreatic tumor cell growth remains to be fully elucidated. The recent use of primary human cells to study Ras-mediated oncogenesis provides important model cell systems to dissect this mechanism. We have used a model of telomerase-immortalized human pancreatic duct-derived cells (E6/E7/st) to study mechanisms of Ras growth transformation. First, we found that human papillomavirus E6 and E7 oncogenes, which block the function of the p53 and Rb tumor suppressors, respectively, and SV40 small t antigen were required to allow mutant K-Ras(12D) growth transformation. Second, K-Ras(12D) caused growth transformation in vitro, including enhanced growth rate and loss of density dependency for growth, anchorage independence, and invasion through reconstituted basement membrane proteins, and tumorigenic transformation in vivo. Third, we determined that the Raf, phosphatidylinositol 3-kinase (PI3K), and Ral guanine nucleotide exchange factor effector pathways were activated, although extracellular signal-regulated kinase (ERK) activity was not up-regulated persistently. Finally, pharmacologic inhibition of Raf/mitogen-activated protein kinase/ERK and PI3K signaling impaired K-Ras-induced anchorage-independent growth and invasion. In summary, our studies established, characterized, and validated E6/E7/st cells for the study of Ras-induced oncogenesis.

Original languageEnglish (US)
Pages (from-to)2098-2106
Number of pages9
JournalCancer Research
Volume67
Issue number5
DOIs
StatePublished - Mar 1 2007

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Phosphatidylinositol 3-Kinase
Growth
Extracellular Signal-Regulated MAP Kinases
ral Guanine Nucleotide Exchange Factor
Carcinogenesis
Neoplastic Cell Transformation
ras Genes
Pancreatic Ducts
Telomerase
Mitogen-Activated Protein Kinases
Growth and Development
Oncogenes
Basement Membrane
Neoplasms
Membrane Proteins
Adenocarcinoma
Antigens

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

K-Ras promotes growth transformation and invasion of immortalized human pancreatic cells by raf and phosphatidylinositol 3-kinase signaling. / Campbell, Paul M.; Groehler, Angela L.; Lee, Kwang M.; Ouellette, Michel M; Khazak, Vladimir; Der, Channing J.

In: Cancer Research, Vol. 67, No. 5, 01.03.2007, p. 2098-2106.

Research output: Contribution to journalArticle

Campbell, Paul M. ; Groehler, Angela L. ; Lee, Kwang M. ; Ouellette, Michel M ; Khazak, Vladimir ; Der, Channing J. / K-Ras promotes growth transformation and invasion of immortalized human pancreatic cells by raf and phosphatidylinositol 3-kinase signaling. In: Cancer Research. 2007 ; Vol. 67, No. 5. pp. 2098-2106.
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