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.