title: C-FLIP promotes the motility of cancer cells by activating FAK and ERK, and increasing MMP-9 expression.
abstract: We examined the role of c-FLIP in the motility of HeLa cells. A small interfering RNA (siRNA) directed against c-FLIP inhibited the adhesion and motility of the cells without affecting their growth rate. The long form of c-FLIP (c-FLIPL), but not the short form (c-FLIPS), enhanced adhesion and motility. Downregulation of c-FLIPL with siRNA decreased phosphorylation of FAK and ERK, while overexpression of c-FLIPL increased their phosphorylation. Overexpression of FAK activated ERK, and enhanced the motility of HeLa cells. FRNK, an inhibitory fragment of FAK, inhibited ERK and decreased motility. Inhibition of ERK also significantly suppressed c-FLIPL-promoted motility. Inhibition of ROCK by Y27632 suppressed the c-FLIPL-promoted motility by reducing phosphorylation of FAK and ERK. Overexpression of c-FLIPL increased the expression and secretion of MMP-9, and inhibition of MMP-9 by Ilomastat reduced c-FLIPL- promoted cell motility. A caspase-like domain (amino acids 222-376) was found to be necessary for the c-FLIPL-promoted cell motility. We conclude that c-FLIPL promotes the motility of HeLa cells by activating FAK and ERK, and increasing MMP-9 expression.
authors.affiliation: School of Biological Sciences, College of Natural Sciences, Kangwon National University, Chunchon 200-701, Korea.
authors.forename: Deokbum
authors.initials: D
authors.lastname: Park
authors.forename: Eunsook
authors.initials: E
authors.lastname: Shim
authors.forename: Youngmi
authors.initials: Y
authors.lastname: Kim
authors.forename: Young Myeong
authors.initials: YM
authors.lastname: Kim
authors.forename: Hansoo
authors.initials: H
authors.lastname: Lee
authors.forename: Jongseon
authors.initials: J
authors.lastname: Choe
authors.forename: Dongmin
authors.initials: D
authors.lastname: Kang
authors.forename: Yun-Sil
authors.initials: YS
authors.lastname: Lee
authors.forename: Dooil
authors.initials: D
authors.lastname: Jeoung
mesh_terms: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000737:chemistry / Q000378:metabolism*; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism*; D051416:Focal Adhesion Protein-Tyrosine Kinases / Q000378:metabolism*; D006367:HeLa Cells; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism*; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D009369:Neoplasms / Q000201:enzymology* / Q000473:pathology*; D010766:Phosphorylation / Q000187:drug effects; D020033:Protein Isoforms / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D034741:RNA, Small Interfering / Q000378:metabolism; D014162:Transfection; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors
chemical_list: D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; C506386:CFLAR protein, human; D016326:Extracellular Matrix Proteins; D020033:Protein Isoforms; D047428:Protein Kinase Inhibitors; D034741:RNA, Small Interfering; D051416:Focal Adhesion Protein-Tyrosine Kinases; D054460:rho-Associated Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020780:Matrix Metalloproteinase 9