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DLC-1 suppresses non-small cell lung cancer growth and invasion by RhoGAP-dependent and independent mechanisms
Cited 111 time in
Web of Science
Cited 112 time in Scopus
- Authors
- Issue Date
- 2007-10-13
- Publisher
- Wiley-Blackwell
- Citation
- Mol Carcinog. 2008 May;47(5):326-37.
- Keywords
- 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
- Abstract
- 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.
- ISSN
- 1098-2744 (Electronic)
- Language
- English
- URI
- http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17932950
https://hdl.handle.net/10371/23850
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