Activated Rac1 regulates the degradation of IκBα and the nuclear translocation of STAT3-NFκB complexes in starved cancer cells.
Activated Rac1 regulates the degradation of IκBα and the nuclear translocation of STAT3-NFκB complexes in starved cancer cells.
复制标题
DOI：
10.1038/emm.2016.17
复制
发表时间：
2016-05-06
影响因子：
12.8
通讯作者：
Yoon S
中科院分区：
文献类型：
--
作者：
Kim SJ;Yoon S
在几种人类肿瘤中，信号转导和转录激活因子3（STAT 3）和核因子κB（NFκB）被激活并相互作用;这些STAT 3-NFκB复合物如何转运到细胞核尚不完全清楚。在本研究中，我们发现Rac 1在饥饿的癌细胞中被激活，并且激活的Rac 1与STAT 3和NFκB共存。Rac 1敲低和显性负性突变体Rac 1 N19的过表达抑制了NFκB抑制剂IκBα的降解。MG 132是一种泛素蛋白酶体通路抑制剂，可增加非磷酸化IκBα的量，但不增加丝氨酸磷酸化IκBα的量，表明饥饿癌细胞中Rac 1对IκBα的降解不依赖于IKK对IκBα丝氨酸磷酸化。Rac 1敲低也抑制了STAT 3-NFκB复合物的核转位，表明这种转位需要活化的Rac 1。我们还证明突变型STAT 3 Y 705 F可以与NFκB形成复合物，并且这些未磷酸化的STAT 3-NFκB复合物在饥饿的癌细胞中移位到细胞核中并上调NFκB的活性，这表明STAT 3的磷酸化不是其移位所必需的。据我们所知，这是第一项证明Rac 1在饥饿癌细胞中STAT 3-NFκB复合物功能中的关键作用的研究，这意味着靶向Rac 1可能在癌症治疗中具有未来的治疗意义。
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.