Matrix metalloproteinase-10 is a critical effector of protein kinase Cι-Par6α-mediated lung cancer

L. A. Frederick, J. A. Matthews, L. Jamieson, V. Justilien, E. A. Thompson, D. C. Radisky, A. P. Fields

Research output: Contribution to journalArticle

67 Scopus citations

Abstract

Protein kinase Cι (PKCι) drives transformed growth of non-small cell lung cancer (NSCLC) cells through the Rho family GTPase Rac1. We show here that PKCι activates Rac1 in NSCLC cells by formation of a PKCι-Par6α complex that drives anchorage-independent growth and invasion through activation of matrix metalloproteinase-10 (MMP-10) expression. RNAi-mediated knockdown of PKCι, Par6α or Rac1 expression inhibits NSCLC transformation and MMP-10 expression in vitro. Expression of wild-type Par6α in Par6α-deficient cells restores transformation and MMP-10 expression, whereas expression of Par6α mutants that either cannot bind PKCι (Par6α-K19A) or couple to Rac1 (Par6α-ΔCRIB) do not. Knockdown of MMP-10 expression blocks anchorage-independent growth and invasion of NSCLC cells and addition of catalytically active MMP-10 to PKCι- or Par6α-deficient cells restores anchorage-independent growth and invasion. Dominant-negative PKCι inhibits tumorigenicity and MMP-10 expression in subcutaneous NSCLC tumors. MMP-10 and PKCι are coordinately overexpressed in primary NSCLC tumors, and tumor MMP-10 expression predicts poor survival in NSCLC patients. Our data define a PKCι-Par6α-Rac1 signaling axis that drives anchorage-independent growth and invasion of NSCLC cells through induction of MMP-10 expression.

Original languageEnglish (US)
Pages (from-to)4841-4853
Number of pages13
JournalOncogene
Volume27
Issue number35
DOIs
StatePublished - Aug 14 2008

Keywords

  • Anchorage-independent growth
  • Cellular invasion
  • Non-small cell lung cancer
  • PB1 domain
  • Rac1

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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