S-Space College of Medicine/School of Medicine (의과대학/대학원) Internal Medicine (내과학전공) Journal Papers (저널논문_내과학전공)
DLC-1 suppresses non-small cell lung cancer growth and invasion by RhoGAP-dependent and independent mechanisms
- Healy, Kevin D; Hodgson, Louis; Kim, Tai-Young; Shutes, Adam; Maddileti, Savitri; Juliano, Rudolph L; Hahn, Klaus M; Harden, T Kendall; Bang, Yung-Jue; Der, Channing J
- Issue Date
- Mol Carcinog. 2008;47(5):326-337
- Carcinoma, Non-Small-Cell Lung/metabolism/pathology/*prevention & control; Cell Movement; Collagen/metabolism; DNA Primers; Drug Combinations; Gene Expression Regulation, Neoplastic; Genes, Tumor Suppressor/physiology; Guanosine Triphosphate/metabolism; Humans; Hydrolysis; Laminin/metabolism; Lung Neoplasms/metabolism/pathology/*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/*metabolism; rhoA GTP-Binding Protein/genetics/*metabolism; rhoB GTP-Binding Protein/genetics/*metabolism
- 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.
- 1098-2744 (Electronic)
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