DLC-1 suppresses non-small cell lung cancer growth and invasion by RhoGAP-dependent and independent mechanisms

Mol Carcinog. 2008 May;47(5):326-37. doi: 10.1002/mc.20389.


Expression of the tumor suppressor deleted in liver cancer-1 (DLC-1) is lost in non-small cell lung (NSCLC) and other human carcinomas, and ectopic DLC-1 expression dramatically reduces proliferation and tumorigenicity. DLC-1 is a multi-domain protein that includes a Rho GTPase activating protein (RhoGAP) domain which has been hypothesized to be the basis of its tumor suppressive actions. To address the importance of the RhoGAP function of DLC-1 in tumor suppression, we performed biochemical and biological studies evaluating DLC-1 in NSCLC. Full-length DLC-1 exhibited strong GAP activity for RhoA as well as RhoB and RhoC, but only very limited activity for Cdc42 in vitro. In contrast, the isolated RhoGAP domain showed 5- to 20-fold enhanced activity for RhoA, RhoB, RhoC, and Cdc42. DLC-1 protein expression was absent in six of nine NSCLC cell lines. Restoration of DLC-1 expression in DLC-1-deficient NSCLC cell lines reduced RhoA activity, and experiments with a RhoA biosensor demonstrated that DLC-1 dramatically reduces RhoA activity at the leading edge of cellular protrusions. Furthermore, DLC-1 expression in NSCLC cell lines impaired both anchorage-dependent and -independent growth, as well as invasion in vitro. Surprisingly, we found that the anti-tumor activity of DLC-1 was due to both RhoGAP-dependent and -independent activities. Unlike the rat homologue p122RhoGAP, DLC-1 was not capable of activating the phospholipid hydrolysis activity of phospholipase C-delta1. Combined, these studies provide information on the mechanism of DLC-1 function and regulation, and further support the role of DLC-1 tumor suppression in NSCLC.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinoma, Non-Small-Cell Lung / metabolism
  • Carcinoma, Non-Small-Cell Lung / pathology
  • Carcinoma, Non-Small-Cell Lung / prevention & control*
  • Cell Movement
  • Collagen / metabolism
  • DNA Primers
  • Drug Combinations
  • GTPase-Activating Proteins
  • Gene Expression Regulation, Neoplastic
  • Genes, Tumor Suppressor / physiology
  • Guanosine Triphosphate / metabolism
  • Humans
  • Hydrolysis
  • Laminin / metabolism
  • Lung Neoplasms / metabolism
  • Lung Neoplasms / pathology
  • Lung Neoplasms / prevention & control*
  • Neoplasm Invasiveness
  • Phospholipase C delta / metabolism
  • Polymerase Chain Reaction
  • Proteoglycans / metabolism
  • Tumor Cells, Cultured
  • Tumor Stem Cell Assay
  • Tumor Suppressor Proteins / physiology*
  • rho GTP-Binding Proteins / genetics
  • rho GTP-Binding Proteins / metabolism*
  • rhoA GTP-Binding Protein / genetics
  • rhoA GTP-Binding Protein / metabolism*
  • rhoB GTP-Binding Protein / genetics
  • rhoB GTP-Binding Protein / metabolism*
  • rhoC GTP-Binding Protein


  • DLC1 protein, human
  • DNA Primers
  • Drug Combinations
  • GTPase-Activating Proteins
  • Laminin
  • Proteoglycans
  • Tumor Suppressor Proteins
  • matrigel
  • Guanosine Triphosphate
  • Collagen
  • PLCD1 protein, human
  • Phospholipase C delta
  • RHOC protein, human
  • rho GTP-Binding Proteins
  • rhoA GTP-Binding Protein
  • rhoB GTP-Binding Protein
  • rhoC GTP-Binding Protein