Singh Kritarth, Poteryakhina Anastasia, Zheltukhin Andrei, Bhatelia Khyati, Prajapati Paresh, Sripada Lakshmi, Tomar Dhanendra, Singh Rochika, Singh Arun K, Chumakov Peter M, Singh Rajesh
Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India; Department of Cell Biology, School of Biological Sciences and Biotechnology, Indian Institute of Advanced Research, Gandhinagar, India.
Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
Biochim Biophys Acta. 2015 May;1853(5):1073-86. doi: 10.1016/j.bbamcr.2015.01.016. Epub 2015 Jan 30.
Chronic inflammation in tumor microenvironment plays an important role at different stages of tumor development. The specific mechanisms of the association and its role in providing a survival advantage to the tumor cells are not well understood. Mitochondria are emerging as a central platform for the assembly of signaling complexes regulating inflammatory pathways, including the activation of type-I IFN and NF-κB. These complexes in turn may affect metabolic functions of mitochondria and promote tumorigenesis. NLRX1, a mitochondrial NOD-like receptor protein, regulate inflammatory pathways, however its role in regulation of cross talk of cell death and metabolism and its implication in tumorigenesis is not well understood. Here we demonstrate that NLRX1 sensitizes cells to TNF-α induced cell death by activating Caspase-8. In the presence of TNF-α, NLRX1 and active subunits of Caspase-8 are preferentially localized to mitochondria and regulate the mitochondrial ROS generation. NLRX1 regulates mitochondrial Complex I and Complex III activities to maintain ATP levels in the presence of TNF-α. The expression of NLRX1 compromises clonogenicity, anchorage-independent growth, migration of cancer cells in vitro and suppresses tumorigenicity in vivo in nude mice. We conclude that NLRX1 acts as a potential tumor suppressor by regulating the TNF-α induced cell death and metabolism.
肿瘤微环境中的慢性炎症在肿瘤发展的不同阶段发挥着重要作用。其关联的具体机制及其在为肿瘤细胞提供生存优势方面的作用尚不清楚。线粒体正成为调节炎症信号通路（包括I型干扰素和核因子κB的激活）的信号复合物组装的核心平台。这些复合物进而可能影响线粒体的代谢功能并促进肿瘤发生。NLRX1是一种线粒体NOD样受体蛋白，可调节炎症信号通路，但其在调节细胞死亡与代谢的相互作用以及在肿瘤发生中的作用尚不清楚。在此，我们证明NLRX1通过激活半胱天冬酶-8使细胞对肿瘤坏死因子-α诱导的细胞死亡敏感。在肿瘤坏死因子-α存在的情况下，NLRX1和半胱天冬酶-8的活性亚基优先定位于线粒体并调节线粒体活性氧的产生。NLRX1调节线粒体复合物I和复合物III的活性，以在肿瘤坏死因子-α存在的情况下维持ATP水平。NLRX1的表达损害了癌细胞在体外的克隆形成能力、非锚定依赖性生长、迁移能力，并在裸鼠体内抑制了肿瘤发生。我们得出结论，NLRX1通过调节肿瘤坏死因子-α诱导的细胞死亡和代谢而作为一种潜在的肿瘤抑制因子发挥作用。
