title: 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.
authors.affiliation: Department of Pharmacology and Toxicology, University of Ulm, Albert-Einstein-Allee 11, 89081 Ulm, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Dreissigacker
authors.forename: Meike S
authors.initials: MS
authors.lastname: Mueller
authors.forename: Monika
authors.initials: M
authors.lastname: Unger
authors.forename: Patrizia
authors.initials: P
authors.lastname: Siegert
authors.forename: Felicitas
authors.initials: F
authors.lastname: Genze
authors.forename: Peter
authors.initials: P
authors.lastname: Gierschik
authors.forename: Klaudia
authors.initials: K
authors.lastname: Giehl
mesh_terms: D000818:Animals; D002465:Cell Movement; D002645:Chickens; D003599:Cytoskeleton / Q000473:pathology; D015536:Down-Regulation / Q000235:genetics*; D004789:Enzyme Activation; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D015689:Oncogene Protein p21(ras) / Q000378:metabolism*; D010190:Pancreatic Neoplasms / Q000473:pathology*; D021381:Protein Transport; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
chemical_list: C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D015689:Oncogene Protein p21(ras); D020830:rac1 GTP-Binding Protein; D020742:rhoA GTP-Binding Protein