Open AccessMatrix metalloproteinase-10 is a critical effector of protein kinase Cι-Par6α-mediated lung cancer
Author(s) -
Lori Frederick,
Jason A. Matthews,
Lee Jamieson,
Verline Justilien,
E. Aubrey Thompson,
Derek C. Radisky,
Alan P. Fields
Publication year - 2008
Publication title -
oncogene
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.395
H-Index - 342
eISSN - 1476-5594
pISSN - 0950-9232
DOI - 10.1038/onc.2008.119
Subject(s) - biology , effector , lung cancer , matrix metalloproteinase , cancer , carcinogenesis , cancer research , microbiology and biotechnology , medicine , genetics
Protein kinase Ciota (PKCiota) drives transformed growth of non-small cell lung cancer (NSCLC) cells through the Rho family GTPase Rac1. We show here that PKCiota activates Rac1 in NSCLC cells by formation of a PKCiota-Par6alpha complex that drives anchorage-independent growth and invasion through activation of matrix metalloproteinase-10 (MMP-10) expression. RNAi-mediated knockdown of PKCiota, Par6alpha or Rac1 expression inhibits NSCLC transformation and MMP-10 expression in vitro. Expression of wild-type Par6alpha in Par6alpha-deficient cells restores transformation and MMP-10 expression, whereas expression of Par6alpha mutants that either cannot bind PKCiota (Par6alpha-K19A) or couple to Rac1 (Par6alpha-DeltaCRIB) do not. Knockdown of MMP-10 expression blocks anchorage-independent growth and invasion of NSCLC cells and addition of catalytically active MMP-10 to PKCiota- or Par6alpha-deficient cells restores anchorage-independent growth and invasion. Dominant-negative PKCiota inhibits tumorigenicity and MMP-10 expression in subcutaneous NSCLC tumors. MMP-10 and PKCiota are coordinately overexpressed in primary NSCLC tumors, and tumor MMP-10 expression predicts poor survival in NSCLC patients. Our data define a PKCiota-Par6alpha-Rac1 signaling axis that drives anchorage-independent growth and invasion of NSCLC cells through induction of MMP-10 expression.