Cytoskeletal-associated signal proteins and their downstream effectors are a common pathway for signal transduction from the extracellular matrix, soluble growth factors and physical forces, such as strain and shear stress. The effects of forces generated by increases in extracellular pressure are less well understood but may act via similar pathways. The classic pathway for initiating outside-in signaling is through the binding of cells to extracellular matrix proteins via various integrins. The mechanisms through which intracellular events alter integrin-mediated cell adhesion to matrix proteins, inside-out signaling, are less well understood. Preliminary studies in four colon cancer cell lines and primary cells from 12 human colon tumors suggest that increases in ambient pressure as low as 10mmHg stimulate colon cancer cell, cation dependant adhesiveness. This occurs synergistically with an adhesion promoting factor in serum. Based on preliminary data and what is known about physical force transduction and inside-out signaling in other cell types, the authors hypothesize that increased extracellular pressure initiates a cytoskeletally associated tyrosine kinase mediated signal transduction cascade involving focal adhesion kinase and members of the MAPK family which alters malignant colonocyte integrin binding. This proposal seeks to further define the mechanism by which pressure stimulates adhesion. The authors will identify agents that prevent pressure-stimulated tumor cell adhesion. In the study of these FAK and MAPK enzymes, the basis for a new pathway which regulates cell adhesiveness may be found.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK060771-04
Application #
6723735
Study Section
Surgery and Bioengineering Study Section (SB)
Program Officer
Hamilton, Frank A
Project Start
2001-05-01
Project End
2005-08-31
Budget Start
2004-05-01
Budget End
2005-08-31
Support Year
4
Fiscal Year
2004
Total Cost
$283,100
Indirect Cost
Name
Wayne State University
Department
Surgery
Type
Schools of Medicine
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Basson, M D; Zeng, B; Wang, S (2015) Akt1 binds focal adhesion kinase via the Akt1 kinase domain independently of the pleckstrin homology domain. J Physiol Pharmacol 66:701-9
Basson, Marc D; Zeng, Bixi; Downey, Christina et al. (2015) Increased extracellular pressure stimulates tumor proliferation by a mechanosensitive calcium channel and PKC-?. Mol Oncol 9:513-26
Patterson, Kevin C; Yang, Ruiguo; Zeng, Bixi et al. (2013) Measurement of cationic and intracellular modulation of integrin binding affinity by AFM-based nanorobot. Biophys J 105:40-7
Chaturvedi, Lakshmi S; Zhang, Ping; Basson, Marc D (2012) Effects of extracellular pressure and alcohol on the microglial response to inflammatory stimulation. Am J Surg 204:602-6
Downey, Christina; Craig, David H; Basson, Marc D (2011) Isoform-specific modulation of pressure-stimulated cancer cell proliferation and adhesion by ?-actinin. Am J Surg 202:520-3
Wang, Shouye; Basson, Marc D (2011) Protein kinase B/AKT and focal adhesion kinase: two close signaling partners in cancer. Anticancer Agents Med Chem 11:993-1002
Yu, Guangxiang; Dymond, Michael; Yuan, Lisi et al. (2011) Propofol's effects on phagocytosis, proliferation, nitrate production, and cytokine secretion in pressure-stimulated microglial cells. Surgery 150:887-96
Wang, Shouye; Basson, Marc D (2011) Akt directly regulates focal adhesion kinase through association and serine phosphorylation: implication for pressure-induced colon cancer metastasis. Am J Physiol Cell Physiol 300:C657-70
Perry, Brandon C; Wang, Shouye; Basson, Marc D (2010) Extracellular pressure stimulates adhesion of sarcoma cells via activation of focal adhesion kinase and Akt. Am J Surg 200:610-4
Opreanu, Razvan C; Kuhn, Donald; Basson, Marc D (2010) Influence of alcohol on mortality in traumatic brain injury. J Am Coll Surg 210:997-1007

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