C-FLIP Promotes the Motility of Cancer Cells by Activating FAK and ERK, and Increasing MMP-9 Expression

  • Park, Deokbum (School of Biological Sciences, College of Natural Sciences, Kangwon National University) ;
  • Shim, Eunsook (School of Biological Sciences, College of Natural Sciences, Kangwon National University) ;
  • Kim, Youngmi (School of Biological Sciences, College of Natural Sciences, Kangwon National University) ;
  • Kim, Young Myeong (School of Medicine, Kangwon National University) ;
  • Lee, Hansoo (School of Biological Sciences, College of Natural Sciences, Kangwon National University) ;
  • Choe, Jongseon (School of Medicine, Kangwon National University) ;
  • Kang, Dongmin (Korea Basic Science Institute, Chunchon Center) ;
  • Lee, Yun-Sil (Laboratory of Radiation Effect, Division of Radiation Biology, Korea Institute of Radiological and Medical Sciences) ;
  • Jeoung, Dooil (School of Biological Sciences, College of Natural Sciences, Kangwon National University)
  • Received : 2007.06.04
  • Accepted : 2007.09.14
  • Published : 2008.04.30

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 ($c-FLIP_L$), but not the short form ($c-FLIP_S$), enhanced adhesion and motility. Downregulation of $c-FLIP_L$ with siRNA decreased phosphorylation of FAK and ERK, while overexpression of $c-FLIP_L$ 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 $c-FLIP_L$-promoted motility. Inhibition of ROCK by Y27632 suppressed the $c-FLIP_L$-promoted motility by reducing phosphorylation of FAK and ERK. Overexpression of $c-FLIP_L$ increased the expression and secretion of MMP-9, and inhibition of MMP-9 by Ilomastat reduced $c-FLIP_L$- promoted cell motility. A caspase-like domain (amino acids 222-376) was found to be necessary for the $c-FLIP_L$-promoted cell motility. We conclude that $c-FLIP_L$ promotes the motility of HeLa cells by activating FAK and ERK, and increasing MMP-9 expression.

Keywords

C-FLIP;ERK;FAK;MMP-9;Motility

Acknowledgement

Supported by : Korea Science and Engineering Foundation, Korea Research Foundation, Ministry of Health and Welfare, Ministry of Science and Technology

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