Faculty Collaboration Database

SmgGDS regulates cell proliferation, migration, and NF-kappaB transcriptional activity in non-small cell lung carcinoma. J Biol Chem 2008 Jan 11;283(2):963-76

Date

10/24/2007

Pubmed ID

17951244

DOI

10.1074/jbc.M707526200

Scopus ID

2-s2.0-38149140259 (requires institutional sign-in at Scopus site)   59 Citations

Abstract

Non-small cell lung carcinoma (NSCLC) is promoted by the increased activities of several small GTPases, including K-Ras4B, Rap1A, Rap1B, RhoC, and Rac1. SmgGDS is an unusual guanine nucleotide exchange factor that activates many of these small GTPases, and thus may promote NSCLC development or progression. We report here that SmgGDS protein levels are elevated in NSCLC tumors, compared with normal lung tissue from the same patients or from individuals without cancer. To characterize SmgGDS functions in NSCLC, we tested the effects of silencing SmgGDS expression by transfecting cultured NSCLC cells with SmgGDS small interfering RNA (siRNA). Cells with silenced SmgGDS expression form fewer colonies in soft agar, do not proliferate in culture due to an arrest in G(1) phase, and exhibit disrupted myosin organization and reduced cell migration. The transcriptional activity of NF-kappaB in NSCLC cells is diminished by transfecting the cells with SmgGDS siRNA, and enhanced by transfecting the cells with a cDNA encoding SmgGDS. Because RhoA is a major substrate for SmgGDS, we investigated whether diminished RhoA expression mimics the effects of diminished SmgGDS expression. Silencing RhoA expression with RhoA siRNA disrupts myosin organization, but only moderately decreases cell proliferation and does not inhibit migration. Our finding that the aggressive NSCLC phenotype is more effectively suppressed by silencing SmgGDS than by silencing RhoA is consistent with the ability of SmgGDS to regulate multiple small GTPases in addition to RhoA. These results demonstrate that SmgGDS promotes the malignant NSCLC phenotype and is an intriguing therapeutic target in NSCLC.

Author List

Tew GW, Lorimer EL, Berg TJ, Zhi H, Li R, Williams CL

Author

Carol L. Williams PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Carcinoma, Non-Small-Cell Lung
Cell Division
Cell Line, Tumor
Cell Movement
Guanine Nucleotide Exchange Factors
Humans
Lung Neoplasms
NF-kappa B
RNA, Neoplasm
RNA, Small Interfering
Transcription, Genetic
Transfection
rhoA GTP-Binding Protein