Document Detail


Interplay between β1-integrin and Rho signaling regulates differential scattering and motility of pancreatic cancer cells by snail and Slug proteins.
MedLine Citation:
PMID:  22232555     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The Snail family of transcription factors has been implicated in pancreatic cancer progression. We recently showed that Snail (Snai1) promotes membrane-type 1 matrix metalloproteinase (MT1-MMP)- and ERK1/2-dependent scattering of pancreatic cancer cells in three-dimensional type I collagen. In this study, we examine the role of Slug (Snai2) in regulating pancreatic cancer cell scattering in three-dimensional type I collagen. Although Slug increased MT1-MMP expression and ERK1/2 activity, Slug-expressing cells failed to scatter in three-dimensional collagen. Moreover, in contrast to Snail-expressing cells, Slug-expressing cells did not demonstrate increased collagen I binding, collagen I-driven motility, or α2β1-integrin expression. Significantly, inhibiting β1-integrin function decreased migration and scattering of Snail-expressing cells in three-dimensional collagen. As Rho GTPases have been implicated in invasion and migration, we also analyzed the contribution of Rac1 and Rho signaling to the differential migration and scattering of pancreatic cancer cells. Snail-induced migration and scattering were attenuated by Rac1 inhibition. In contrast, inhibiting Rho-associated kinase ROCK1/2 increased migration and scattering of Slug-expressing cells in three-dimensional collagen and thus phenocopied the effects of Snail in pancreatic cancer cells. Additionally, the increased migration and scattering in three-dimensional collagen of Slug-expressing cells following ROCK1/2 inhibition was dependent on β1-integrin function. Overall, these results demonstrate differential effects of Snail and Slug in pancreatic cancer and identify the interplay between Rho signaling and β1-integrin that functions to regulate the differential scattering and migration of Snail- and Slug-expressing pancreatic cancer cells.
Authors:
Mario A Shields; Seth B Krantz; David J Bentrem; Surabhi Dangi-Garimella; Hidayatullah G Munshi
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.     Date:  2012-01-09
Journal Detail:
Title:  The Journal of biological chemistry     Volume:  287     ISSN:  1083-351X     ISO Abbreviation:  J. Biol. Chem.     Publication Date:  2012 Feb 
Date Detail:
Created Date:  2012-02-27     Completed Date:  2012-04-25     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  2985121R     Medline TA:  J Biol Chem     Country:  United States    
Other Details:
Languages:  eng     Pagination:  6218-29     Citation Subset:  IM    
Affiliation:
Division of Hematology/Oncology, Department of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
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MeSH Terms
Descriptor/Qualifier:
Antigens, CD29 / metabolism*
Cell Movement / physiology*
Collagen Type I / metabolism
Humans
Matrix Metalloproteinase 14 / metabolism
Mitogen-Activated Protein Kinase 1 / metabolism
Mitogen-Activated Protein Kinase 3 / metabolism
Pancreatic Neoplasms / metabolism*,  pathology
Phosphorylation / physiology
Signal Transduction / physiology*
Tissue Inhibitor of Metalloproteinase-2 / metabolism
Transcription Factors / metabolism*
Tumor Cells, Cultured
rac1 GTP-Binding Protein / metabolism
rho-Associated Kinases / metabolism*
Grant Support
ID/Acronym/Agency:
R01CA126888/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antigens, CD29; 0/Collagen Type I; 0/RAC1 protein, human; 0/ROCK1 protein, human; 0/ROCK2 protein, human; 0/TIMP2 protein, human; 0/Transcription Factors; 0/snail family transcription factors; 127497-59-0/Tissue Inhibitor of Metalloproteinase-2; EC 2.7.11.1/rho-Associated Kinases; EC 2.7.11.24/MAPK1 protein, human; EC 2.7.11.24/Mitogen-Activated Protein Kinase 1; EC 2.7.11.24/Mitogen-Activated Protein Kinase 3; EC 3.4.24.80/MMP14 protein, human; EC 3.4.24.80/Matrix Metalloproteinase 14; EC 3.6.5.2/rac1 GTP-Binding Protein
Comments/Corrections

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