Endotoxin/lipopolysaccharide activates NF-kappa B and enhances tumor cell adhesion and invasion through a beta 1 integrin-dependent mechanism.
Beta(1) integrins play a crucial role in supporting tumor cell attachment to and invasion into the extracellular matrix. Endotoxin/LPS introduced by surgery has been shown to enhance tumor metastasis in a murine model. Here we show the direct effect of LPS on tumor cell adhesion and invasion in extracellular matrix proteins through a beta(1) integrin-dependent pathway. The human colorectal tumor cell lines SW480 and SW620 constitutively expressed high levels of the beta(1) subunit, whereas various low levels of alpha(1), alpha(2), alpha(4), and alpha(6) expression were detected. SW480 and SW620 did not express membrane-bound CD14; however, LPS in the presence of soluble CD14 (sCD14) significantly up-regulated beta(1) integrin expression; enhanced tumor cell attachment to fibronectin, collagen I, and laminin; and strongly promoted tumor cell invasion through the Matrigel. Anti-beta(1) blocking mAbs (4B4 and 6S6) abrogated LPS- plus sCD14-induced tumor cell adhesion and invasion. Furthermore, LPS, when combined with sCD14, resulted in NF-kappaB activation in both SW480 and SW620 cells. Inhibition of the NF-kappaB pathway significantly attenuated LPS-induced up-regulation of beta(1) integrin expression and prevented tumor cell adhesion and invasion. These results provide direct evidence that although SW480 and SW620 cells do not express membrane-bound CD14, LPS in the presence of sCD14 can activate NF-kappaB, up-regulate beta(1) integrin expression, and subsequently promote tumor cell adhesion and invasion. Moreover, LPS-induced tumor cell attachment to and invasion through extracellular matrix proteins is beta(1) subunit-dependent.
Wang
Jiang Huai
JH
Department of Academic Surgery, National University of Ireland, Cork University Hospital, Ireland. jh.wang@ucc.i.e
Manning
Brian J
BJ
Wu
Qiong Di
QD
Blankson
Siobhan
S
Bouchier-Hayes
D
D
Redmond
H Paul
HP
D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D002448:Cell Adhesion / Q000276:immunology; D002462:Cell Membrane / Q000276:immunology / Q000378:metabolism; D002465:Cell Movement / Q000276:immunology*; D004731:Endotoxins / Q000494:pharmacology*; D006801:Humans; D020672:I-kappa B Proteins / Q000235:genetics; D039302:Integrin alphaVbeta3 / Q000096:biosynthesis; D019012:Integrin beta1 / Q000096:biosynthesis / Q000502:physiology*; D018950:Lipopolysaccharide Receptors / Q000096:biosynthesis / Q000378:metabolism / Q000494:pharmacology; D008070:Lipopolysaccharides / Q000494:pharmacology*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010455:Peptides / Q000494:pharmacology; D015398:Signal Transduction / Q000276:immunology; D012995:Solubility; D014162:Transfection; D014407:Tumor Cells, Cultured / Q000276:immunology / Q000378:metabolism / Q000473:pathology*; D015854:Up-Regulation / Q000276:immunology
D000276:Adjuvants, Immunologic; D004731:Endotoxins; D020672:I-kappa B Proteins; D039302:Integrin alphaVbeta3; D019012:Integrin beta1; D018950:Lipopolysaccharide Receptors; D008070:Lipopolysaccharides; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D010455:Peptides; C118258:SN50 peptide; D000072000:NF-KappaB Inhibitor alpha