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Activated Rac1 regulates the degradation of IkappaBalpha and the nuclear translocation of STAT3-NFkappaB complexes in starved cancer cells

Authors
Kim, SJ | Yoon, S
Citation
Experimental & molecular medicine, 48. : e231-e231, 2016
Journal Title
Experimental & molecular medicine
ISSN
1226-36132092-6413
Abstract
In several human tumors, signal transducer and activator of transcription 3 (STAT3) and nuclear factor kappaB (NFkappaB) are activated and interact: how these STAT3-NFkappaB 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 NFkappaB. Rac1 knockdown and overexpression of the dominant-negative mutant Rac1N19 inhibited the degradation of IkappaBalpha, an inhibitor of NFkappaB. MG132, an inhibitor of the ubiquitin proteasome pathway, increased the amount of non-phosphorylated IkappaBalpha, but not serine-phosphorylated IkappaBalpha, indicating that IkappaBalpha degradation by Rac1 in starved cancer cells is independent of IkappaBalpha serine phosphorylation by IKK. Rac1 knockdown also inhibited the nuclear translocation of STAT3-NFkappaB complexes, indicating that this translocation requires activated Rac1. We also demonstrated that the mutant STAT3 Y705F could form complexes with NFkappaB, and these unphosphorylated STAT3-NFkappaB complexes translocated into the nucleus and upregulated the activity of NFkappaB 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-NFkappaB complexes in starved cancer cells and implies that targeting Rac1 may have future therapeutic significance in cancer therapy.
MeSH

DOI
10.1038/emm.2016.17
PMID
27151455
Appears in Collections:
Journal Papers > School of Medicine / Graduate School of Medicine > Physiology
Ajou Authors
윤, 사라
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