title: Activated Rac1 regulates the degradation of IκBα and the nuclear translocation of STAT3-NFκB complexes in starved cancer cells.
abstract: In several human tumors, signal transducer and activator of transcription 3 (STAT3) and nuclear factor κB (NFκB) are activated and interact; how these STAT3-NFκB complexes are transported to the nucleus is not fully understood. In this study, we found that Rac1 was activated in starved cancer cells and that activated Rac1 coexisted with STAT3 and NFκB. Rac1 knockdown and overexpression of the dominant-negative mutant Rac1N19 inhibited the degradation of IκBα, an inhibitor of NFκB. MG132, an inhibitor of the ubiquitin proteasome pathway, increased the amount of non-phosphorylated IκBα, but not serine-phosphorylated IκBα, indicating that IκBα degradation by Rac1 in starved cancer cells is independent of IκBα serine phosphorylation by IKK. Rac1 knockdown also inhibited the nuclear translocation of STAT3-NFκB complexes, indicating that this translocation requires activated Rac1. We also demonstrated that the mutant STAT3 Y705F could form complexes with NFκB, and these unphosphorylated STAT3-NFκB complexes translocated into the nucleus and upregulated the activity of NFκB in starved cancer cells, suggesting that phosphorylation of STAT3 is not essential for its translocation. To our knowledge, this is the first study demonstrating the crucial role of Rac1 in the function of STAT3-NFκB complexes in starved cancer cells and implies that targeting Rac1 may have future therapeutic significance in cancer therapy.
authors.affiliation: Department of Biomedical Sciences, Graduate School, Ajou University, Worldcup-ro, Yeongtong-gu, Gyeonggi-do, Korea.
authors.forename: Sung Joo
authors.initials: SJ
authors.lastname: Kim
authors.affiliation: Department of Physiology, Ajou University School of Medicine, Worldcup-ro, Yeongtong-gu, Gyeonggi-do, Korea.
authors.forename: Sarah
authors.initials: S
authors.lastname: Yoon
mesh_terms: D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D020672:I-kappa B Proteins / Q000378:metabolism*; D000072000:NF-KappaB Inhibitor alpha; D016328:NF-kappa B / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011485:Protein Binding; D021381:Protein Transport; D059748:Proteolysis; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
chemical_list: D020672:I-kappa B Proteins; D016328:NF-kappa B; C000606204:NFKBIA protein, human; D050796:STAT3 Transcription Factor; D000072000:NF-KappaB Inhibitor alpha; D020830:rac1 GTP-Binding Protein