Interplay between β1-integrin and Rho signaling regulates differential scattering and motility of pancreatic cancer cells by snail and Slug proteins.
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.
Division of Hematology/Oncology, Department of Medicine, Northwestern University, Chicago, Illinois 60611, USA.
Mario A
MA
Shields
Seth B
SB
Krantz
David J
DJ
Bentrem
Surabhi
S
Dangi-Garimella
Hidayatullah G
HG
Munshi
D002465:Cell Movement / Q000502:physiology*; D024042:Collagen Type I / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism*; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D010766:Phosphorylation / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*; D000071250:Snail Family Transcription Factors; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D020830:rac1 GTP-Binding Protein / Q000378:metabolism; D054460:rho-Associated Kinases / Q000378:metabolism*
D024042:Collagen Type I; D019012:Integrin beta1; C107953:RAC1 protein, human; C000604407:SNAI1 protein, human; C000604408:SNAI2 protein, human; D000071250:Snail Family Transcription Factors; C560823:TIMP2 protein, human; D014157:Transcription Factors; D019716:Tissue Inhibitor of Metalloproteinase-2; C515851:ROCK1 protein, human; C515852:ROCK2 protein, human; D054460:rho-Associated Kinases; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C507086:MMP14 protein, human; D053511:Matrix Metalloproteinase 14; D020830:rac1 GTP-Binding Protein