title: The role of Rac1 in the regulation of NF-κB activity, cell proliferation, and cell migration in non-small cell lung carcinoma.
abstract: The small GTPase Rac1 regulates many cellular processes, including cytoskeletal reorganization, cell migration, proliferation, and survival. Additionally, Rac1 plays a major role in activating NF-κB-mediated transcription. Both Rac1 and NF-κB regulate many properties of the malignant phenotype, including anchorage-independent proliferation and survival, metastasis, and angiogenesis. Despite these findings, the roles of Rac1and NF-κB in non-small cell lung carcinoma, a leading cause of cancer deaths, have not been thoroughly investigated. Here, we compared the effects of Rac1 siRNA to that of the Rac1 inhibitor NSC23766 on multiple features of the NSCLC malignant phenotype, including NF-κB activity. We show that the siRNA-mediated silencing of Rac1 in lung cancer cells results in decreased cell proliferation and migration. The decrease in proliferation was observed in both anchorage-dependent and anchorage-independent assays. Furthermore, cells with decreased Rac1 expression have a slowed progression through the G 1 phase of the cell cycle. These effects induced by Rac1 siRNA correlated with a decrease in NF-κB transcriptional activity. Additionally, inhibition of NF-κB signaling with BAY 11-7082 inhibited proliferation; indicating that the loss of cell proliferation and migration induced by the silencing of Rac1 expression may be attributed in part to loss of NF-κB activity. Interestingly, treatment with the Rac1 inhibitor NSC23766 strongly inhibits cell proliferation, cell cycle progression, and NF-κB activity in lung cancer cells, to an even greater extent than the inhibition induced by Rac1 siRNA. These findings indicate that Rac1 plays an important role in lung cancer cell proliferation and migration, most likely through its ability to promote NF-κB activity, and highlight Rac1 pathways as therapeutic targets for the treatment of lung cancer.
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Wisconsin, Milwaukee, WI, USA.
authors.forename: Adam
authors.initials: A
authors.lastname: Gastonguay
authors.forename: Tracy
authors.initials: T
authors.lastname: Berg
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Hauser
authors.forename: Nathan
authors.initials: N
authors.lastname: Schuld
authors.forename: Ellen
authors.initials: E
authors.lastname: Lorimer
authors.forename: Carol L
authors.initials: CL
authors.lastname: Williams
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000378:metabolism*; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D020868:Gene Silencing; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009570:Nitriles / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D013450:Sulfones / Q000494:pharmacology; D014158:Transcription, Genetic / Q000187:drug effects; D020830:rac1 GTP-Binding Protein / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*
chemical_list: C434003:3-(4-methylphenylsulfonyl)-2-propenenitrile; D000634:Aminoquinolines; D016328:NF-kappa B; C487513:NSC 23766; D009570:Nitriles; D011743:Pyrimidines; D013450:Sulfones; D020830:rac1 GTP-Binding Protein