MITA modulated autophagy flux promotes cell death in breast cancer cells
MITA modulated autophagy flux promotes cell death in breast cancer cells
复制标题
DOI：
10.1016/j.cellsig.2017.03.024
复制
发表时间：
2017-07-01
影响因子：
4.8
通讯作者：
Singh, Rajesh
中科院分区：
文献类型：
--
作者：
Bhatelia, Khyati;Singh, Kritarth;Singh, Rajesh
炎症和自噬之间的串扰是肿瘤发生过程中观察到的一种新兴现象。 NF-κ B 和 IRF3 的激活在调节参与肿瘤生长和进展的细胞因子中发挥着关键作用。已知先天免疫基因可调节 NF-kappa B 和 IRF3 等主转录因子。先天免疫途径同时调节对肿瘤细胞代谢至关重要的自噬途径的基因。在本研究中，我们研究了先天免疫调节剂 MITA（IRF3 激活调节剂）在自噬调节中的作用及其对乳腺癌细胞死亡的影响。在这里，我们报告 MITA 抑制自噬体与溶酶体的融合，从不同的自噬通量测定中可以明显看出。 MITA 的表达诱导 p62 和 NDP52 易位至线粒体，进一步招募 LC3 进行自噬体形成。 MITA 的表达减少了线粒体数量，并通过增加复合物 I 活性来增强线粒体 ROS。雷帕霉素或 TFEB 表达增强自噬流，使 MITA 诱导的细胞死亡正常化。证据清楚地表明 MITA 调节自噬通量并通过线粒体自噬调节线粒体周转。
The crosstalk between inflammation and autophagy is an emerging phenomenon observed during tumorigenesis. Activation of NF-kappa B and IRF3 plays a key role in the regulation of cytokines that are involved in tumor growth and progression. The genes of innate immunity are known to regulate the master transcription factors like NF-kappa B and IRF3. Innate immunity pathways at the same time regulate the genes of the autophagy pathway which are essential for tumor cell metabolism. In the current study, we studied the role of MITA (Mediator of IRF3 Activation), a regulator of innate immunity, in the regulation of autophagy and its implication in cell death of breast cancer cells. Here, we report that MITA inhibits the fusion of autophagosome with lysosome as evident from different autophagy flux assays. The expression of MITA induces the translocation of p62 and NDP52 to mitochondria which further recruits LC3 for autophagosome formation. The expression of MITA decreased mitochondrial number and enhances mitochondrial ROS by increasing complex-I activity. The enhancement of autophagy flux with rapamycin or TFEB expression normalized MITA induced cell death. The evidences clearly show that MITA regulates autophagy flux and modulates mitochondrial turnover through mitophagy.