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Oncogenic K-Ras down-regulates Rac1 and RhoA activity and enhances migration and invasion of pancreatic carcinoma cells through activation of p38.

Abstract
Activating mutations in the K-ras gene are genetic alterations frequently found in human carcinomas, particularly in pancreatic adenocarcinomas. Mutation of the K-ras gene is thought to be an early and important event in pancreatic tumor initiation, but the precise role of the mutant K-Ras proteins in neoplastic progression is still unknown. In the present study, we have characterized the influence of oncogenic K-Ras on the phenotype and on the signal transduction of epitheloid PANC-1 pancreatic carcinoma cells by generating PANC-1 cell clones, which stably express EGFP(enhanced green fluorescent protein)-K-Ras (V12). EGFP-K-Ras (V12)-expressing cells exhibited a more fibroblastoid cellular phenotype with irregular cell shape and disorganized cytokeratin filaments. Moreover, these cells showed a marked enhancement of their migratory and invasive properties. Stable expression of EGFP-K-Ras (V12) down-regulated the activity of Rac1 and RhoA, resulting in reduced subcortical actin filaments and stress fibers, which might contribute to the epithelial dedifferentiation. Characterization of the activity of mitogen-activated protein kinases revealed that EGFP-K-Ras (V12) enhanced the activity of p38, but did not affect the activities of the Raf/MEK/ERK cascade and JNK. While inhibition of either MEK or JNK activity had no effect on EGFP-K-Ras (V12)-induced migration, inhibition of p38 activity markedly reduced EGFP-K-Ras (V12)-induced migration. Collectively, the results suggest that oncogenic K-Ras enhances the malignant phenotype and identify the mitogen-activated protein kinase p38 as a target to inhibit oncogenic K-Ras-induced pancreatic tumor cell migration.
AuthorsUte Dreissigacker, Meike S Mueller, Monika Unger, Patrizia Siegert, Felicitas Genze, Peter Gierschik, Klaudia Giehl
JournalCellular signalling (Cell Signal) Vol. 18 Issue 8 Pg. 1156-68 (Aug 2006) ISSN: 0898-6568 [Print] England
PMID16257181 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • enhanced green fluorescent protein
  • Green Fluorescent Proteins
  • JNK Mitogen-Activated Protein Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Oncogene Protein p21(ras)
  • rac1 GTP-Binding Protein
  • rhoA GTP-Binding Protein
Topics
  • Animals
  • Cell Movement
  • Chickens
  • Cytoskeleton (pathology)
  • Down-Regulation (genetics)
  • Enzyme Activation
  • Green Fluorescent Proteins (metabolism)
  • Humans
  • JNK Mitogen-Activated Protein Kinases (metabolism)
  • Neoplasm Invasiveness
  • Neoplasm Metastasis
  • Oncogene Protein p21(ras) (metabolism)
  • Pancreatic Neoplasms (pathology)
  • Protein Transport
  • p38 Mitogen-Activated Protein Kinases (metabolism)
  • rac1 GTP-Binding Protein (metabolism)
  • rhoA GTP-Binding Protein (metabolism)

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