Matrix metalloproteinase-10 is a critical effector of protein kinase Ciota-Par6alpha-mediated lung cancer.
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.
Frederick
L A
LA
Department of Cancer Biology, Mayo Clinic College of Medicine, Jacksonville, FL 32224, USA.
Matthews
J A
JA
Jamieson
L
L
Justilien
V
V
Thompson
E A
EA
Radisky
D C
DC
Fields
A P
AP
D048868:Adaptor Proteins, Signal Transducing / Q000502:physiology*; D000818:Animals; D002289:Carcinoma, Non-Small-Cell Lung / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division; D045744:Cell Line, Tumor; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D008175:Lung Neoplasms / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D053506:Matrix Metalloproteinase 10 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D011485:Protein Binding; D011493:Protein Kinase C / Q000378:metabolism*; D034622:RNA Interference; D000099293:Protein Kinase C-lambda
D048868:Adaptor Proteins, Signal Transducing; D007527:Isoenzymes; D053506:Matrix Metalloproteinase 10; D011493:Protein Kinase C; D000099293:Protein Kinase C-lambda; C499657:PARD6A protein, human