NLRX1 acts as tumor suppressor by regulating TNF-α induced apoptosis and metabolism in cancer cells.
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.
['Singh|Kritarth|K|', 'Poteryakhina|Anastasia|A|', 'Zheltukhin|Andrei|A|', 'Bhatelia|Khyati|K|', 'Prajapati|Paresh|P|', 'Sripada|Lakshmi|L|', 'Tomar|Dhanendra|D|', 'Singh|Rochika|R|', 'Singh|Arun K|AK|', 'Chumakov|Peter M|PM|', 'Singh|Rajesh|R|']
D000255:Adenosine Triphosphate D000818:Animals D017209:Apoptosis D063646:Carcinogenesis D053181:Caspase 8 D045744:Cell Line, Tumor D002465:Cell Movement D049109:Cell Proliferation D002999:Clone Cells D045222:Electron Transport Chain Complex Proteins D004789:Enzyme Activation D006801:Humans D008819:Mice, Nude D008928:Mitochondria D024101:Mitochondrial Proteins D009369:Neoplasms D011485:Protein Binding D021381:Protein Transport D017382:Reactive Oxygen Species D012402:Rotenone D014409:Tumor Necrosis Factor-alpha D025521:Tumor Suppressor Proteins
NLRX1 Cancer Inflammation Mitochondria Caspase-8 Metabolic reprogramming