Transendothelial migration of colon carcinoma cells requires expression of E-selectin by endothelial cells and activation of stress-activated protein kinase-2 (SAPK2/p38) in the tumor cells.

Abstract	Adhesion and migration of tumor cells on and through the vascular endothelium are critical steps of the metastatic invasion. We investigated the roles of E-selectin and of stress-activated protein kinase-2 (SAPK2/p38) in modulating endothelial adhesion and transendothelial migration of HT-29 colon carcinoma cells. Tumor necrosis factor alpha (TNF alpha) strongly increased the expression of E-selectin in human umbilical vein endothelial cells (HUVEC). This effect was independent of the activation of SAPK2/p38 induced by TNF alpha. Adhesion of HT-29 cells on a monolayer of HUVEC pretreated with TNF alpha was dependent on E-selectin expression but was independent of SAPK2/p38 activity of both HUVEC and tumor cells. The adhesion of HT-29 cells to E-selectin-expressing HUVEC led to the activation of SAPK2/p38 in the tumor cells as reflected by the increased phosphorylation of the actin-polymerizing factor HSP27 by mitogen-activated protein kinase 2/3, a direct target of SAPK2/p38. Moreover, a recombinant E-selectin/Fc chimera quickly increased the activation of SAPK2/p38 in HT-29 cells. Blocking the increased activity of SAPK2/p38 of HT-29 cells by SB203580 or by expressing a dominant negative form of SAPK2/p38 inhibited their transendothelial migration. Similarly, HeLa cells stably expressing a kinase-inactive mutant of SAPK2/p38 showed a decreased capacity to cross a layer of HUVEC. Overall, our results suggest that the regulation of transendothelial migration of tumor cells involves two essential steps as follows: adhesion to the endothelium through adhesion molecules, such as E-selectin, and increased motogenic potential through adhesion-mediated activation of the SAPK2/p38 pathway.
Authors	J Laferriere, F Houle, M M Taher, K Valerie, J Huot
Journal	The Journal of biological chemistry (J Biol Chem) Vol. 276 Issue 36 Pg. 33762-72 (Sep 07 2001) ISSN: 0021-9258 [Print] United States
PMID	11448946 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References	E-Selectin Enzyme Inhibitors HSP27 Heat-Shock Proteins HSPB1 protein, human Heat-Shock Proteins Imidazoles Molecular Chaperones Neoplasm Proteins Plant Proteins Pyridines Tumor Necrosis Factor-alpha Mitogen-Activated Protein Kinase 1 Mitogen-Activated Protein Kinases p38 Mitogen-Activated Protein Kinases SB 203580 Oxygen
Topics	Cell Adhesion Cell Movement Cells, Cultured Colonic Neoplasms (metabolism) Dose-Response Relationship, Drug E-Selectin (biosynthesis) Endothelium (metabolism) Endothelium, Vascular (cytology) Enzyme Activation Enzyme Inhibitors (pharmacology) HSP27 Heat-Shock Proteins Heat-Shock Proteins Humans Imidazoles (pharmacology) Microscopy, Confocal Mitogen-Activated Protein Kinase 1 (metabolism) Mitogen-Activated Protein Kinases (metabolism) Molecular Chaperones Neoplasm Proteins (metabolism) Oxygen (metabolism) Phosphorylation Plant Proteins Precipitin Tests Protein Binding Pyridines (pharmacology) Time Factors Transfection Tumor Cells, Cultured Tumor Necrosis Factor-alpha (metabolism) Umbilical Veins (metabolism) p38 Mitogen-Activated Protein Kinases

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