The Role of Rac1 on STAT3-NFkappaB complex in Starved Cancer cells

Abstract

Signal transducer and activator of transcription factor 3 (STAT3) and nuclear factor kappa B (NFkB) are activated and interact in several human tumors, but it is not completely clear how the STAT3-NFkB complex is delivered to the nucleus. This study demonstrated that activated Rac1 co-localized with STAT3 and NFkB in cancer cells which had been starved by nutrient depletion. Rac1 induced the degradation of IkBα in cancer cells under nutrient starvation. In contrast, knockdown of Rac1 and overexpression of Rac1N19, as the dominant-negative mutant of Rac1, did not induce IkBα degradation. The degradation of IkBα by Rac1 in starved cancer cells was independent of serine phosphorylation of IkBα by IkB kinase. This demonstrated that the ubiquitin proteasome inhibitor MG132 only increased non-phosphorylated IkBα but did not increase serine-phosphorylated IkB. Knockdown of Rac1 also blocked to translocation of the STAT3-NFkB complex into the nucleus, indicating that activated Rac1 was necessary for this process. In starved cancer cells, STAT3 Y705F, a non-phosphorylated STAT3 mutant, formed a complex with NFkB which was translocated into the nucleus and where the activity of NFkB was induced. These results indicated that nuclear translocation of the STAT3-NFkB complex did not require the phosphorylation of STAT3. This is the first study to show that Rac1 is important in the function of the STAT3-NFkB complex in cancer cells starved by nutrient depletion, indicating that Rac1 is a therapeutic target for cancer treatment.