¹Department of Cancer Biology, Mayo Clinic College of Medicine, Jacksonville, FL, USA

Correspondence: Dr AP Fields, Department of Cancer Biology, Mayo Clinic College of Medicine, Griffin Cancer Research Building, Rm 212, 4500 San Pablo Road, Jacksonville, FA 32224, USA. E-mail: fields.alan@mayo.edu

Received 18 January 2008; Revised 28 February 2008; Accepted 18 March 2008; Published online 21 April 2008.

Abstract

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