Mechanical force modulates global gene expression and beta-catenin signaling in colon cancer cells.
At various stages during embryogenesis and cancer cells are exposed to tension, compression and shear stress; forces that can regulate cell proliferation and differentiation. In the present study, we show that shear stress blocks cell cycle progression in colon cancer cells and regulates the expression of genes linked to the Wnt/beta-catenin, mitogen-activated protein kinase (MAPK) and NFkappaB pathways. The shear stress-induced increase of the secreted Wnt inhibitor DKK1 requires p38 and activation of NFkappaB requires IkappaB kinase-beta. Activation of beta-catenin, important in Wnt signaling and the cause of most colon cancers, is inhibited by shear stress through a pathway involving laminin-5, alpha6beta4 integrin, phosphoinositide 3-kinase (PI 3-kinase) and Rac1 coupled with changes in the distribution of dephosphorylated beta-catenin. These data show that colon cancer cells respond to fluid shear stress by activation of specific signal transduction pathways and genetic regulatory circuits to affect cell proliferation, and indicate that the response of colon cancers to mechanical forces such as fluid shear stress should be taken into account in the management of the disease.
Avvisato
Christopher L
CL
Department of Biomedical Engineering, The Catholic University of America, Washington, DC, USA.
Yang
Xiang
X
Shah
Salim
S
Hoxter
Becky
B
Li
Weiqun
W
Gaynor
Richard
R
Pestell
Richard
R
Tozeren
Aydin
A
Byers
Stephen W
SW
D045744:Cell Line, Tumor; D003110:Colonic Neoplasms / Q000235:genetics / Q000378:metabolism*; D005353:Fibronectins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007797:Laminin / Q000378:metabolism; D053858:Metabolic Networks and Pathways; D016328:NF-kappa B / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D015398:Signal Transduction; D013314:Stress, Mechanical; D051153:Wnt Proteins / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
D005353:Fibronectins; D007797:Laminin; D016328:NF-kappa B; C107953:RAC1 protein, human; D051153:Wnt Proteins; D051176:beta Catenin; D019869:Phosphatidylinositol 3-Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D020830:rac1 GTP-Binding Protein