title: NLRX1 acts as tumor suppressor by regulating TNF-α induced apoptosis and metabolism in cancer cells.
abstract: 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.
authors: 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.
authors: Kritarth
authors: K
authors: Singh
authors: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
authors: Anastasia
authors: A
authors: Poteryakhina
authors: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia.
authors: Andrei
authors: A
authors: Zheltukhin
authors: 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.
authors: Khyati
authors: K
authors: Bhatelia
authors: 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.
authors: Paresh
authors: P
authors: Prajapati
authors: 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.
authors: Lakshmi
authors: L
authors: Sripada
authors: Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India.
authors: Dhanendra
authors: D
authors: Tomar
authors: Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India.
authors: Rochika
authors: R
authors: Singh
authors: Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India.
authors: Arun K
authors: AK
authors: Singh
authors: Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia. Electronic address: peter@chumakov.com.
authors: Peter M
authors: PM
authors: Chumakov
authors: Department of Biochemistry, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India. Electronic address: singhraj1975@gmail.com.
authors: Rajesh
authors: R
authors: Singh
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D063646:Carcinogenesis / Q000378:metabolism / Q000473:pathology; D053181:Caspase 8 / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002999:Clone Cells; D045222:Electron Transport Chain Complex Proteins / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D024101:Mitochondrial Proteins / Q000378:metabolism*; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D012402:Rotenone / Q000494:pharmacology; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D045222:Electron Transport Chain Complex Proteins; D024101:Mitochondrial Proteins; C527006:NLRX1 protein, human; D017382:Reactive Oxygen Species; D014409:Tumor Necrosis Factor-alpha; D025521:Tumor Suppressor Proteins; D012402:Rotenone; D000255:Adenosine Triphosphate; D053181:Caspase 8
keywords: Cancer; Caspase-8; Inflammation; Metabolic reprogramming; Mitochondria; NLRX1