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First published online 17 July 2007
doi: 10.1242/jcs.03476

Journal of Cell Science 120, 2672-2682 (2007)
Published by The Company of Biologists 2007
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Research Article

Mechanical force modulates global gene expression and beta-catenin signaling in colon cancer cells

Christopher L. Avvisato1,2,*, Xiang Yang2,*, Salim Shah2, Becky Hoxter2, Weiqun Li2, Richard Gaynor3, Richard Pestell2, Aydin Tozeren4 and Stephen W. Byers2,{ddagger}

1 Department of Biomedical Engineering, The Catholic University of America, Washington, DC, USA
2 Departments of Oncology, Biochemistry, Molecular and Cellular Biology, Georgetown University School of Medicine and Lombardi Comprehensive Cancer Center, Washington, DC 20007, USA
3 Simmons Cancer Center, University of Texas Southwestern, Dallas, TX, USA
4 School of Engineering, Drexel University, Philadelphia, PA, USA

{ddagger} Author for correspondence (e-mail: byerss{at}georgetown.edu)

Accepted 24 May 2007

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 NF{kappa}B pathways. The shear stress-induced increase of the secreted Wnt inhibitor DKK1 requires p38 and activation of NF{kappa}B requires I{kappa}B 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, {alpha}6beta4 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.

Key words: beta-catenin, Shear stress, Laminin, {alpha}6beta4 integrin, Rac, PI 3-kinase, Cell cycle






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