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

Protein kinase C iota (PKC iota) drives transformed growth of non-small cell lung cancer (NSCLC) cells through the Rho family GTPase Rac1. We show here that PKC iota activates Rac1 in NSCLC cells by formation of a PKC iota-Par6 alpha complex that drives anchorage-independent growth and invasion through activation of matrix metalloproteinase-10 (MMP-10) expression. RNAi-mediated knockdown of PKC iota, Par6 alpha or Rac1 expression inhibits NSCLC transformation and MMP-10 expression in vitro. Expression of wild-type Par6 alpha in Par6 alpha-deficient cells restores transformation and MMP-10 expression, whereas expression of Par6 alpha mutants that either cannot bind PKC iota (Par6 alpha-K19A) or couple to Rac1 (Par6 alpha-Delta CRIB) do not. Knockdown of MMP-10 expression blocks anchorage-independent growth and invasion of NSCLC cells and addition of catalytically active MMP-10 to PKC iota- or Par6 alpha-deficient cells restores anchorage-independent growth and invasion. Dominant-negative PKC iota inhibits tumorigenicity and MMP-10 expression in subcutaneous NSCLC tumors. MMP-10 and PKC iota are coordinately overexpressed in primary NSCLC tumors, and tumor MMP-10 expression predicts poor survival in NSCLC patients. Our data define a PKC iota-Par6 alpha-Rac1 signaling axis that drives anchorage-independent growth and invasion of NSCLC cells through induction of MMP-10 expression.