Abstract
Tumor cells require increased adenosine triphosphate (ATP) to support anabolism and proliferation. The precise mechanisms regulating this process in tumor cells are unknown. Here, we show that the receptor for advanced glycation endproducts (RAGE) and one of its primary ligands, high-mobility group box 1 (HMGB1), are required for optimal mitochondrial function within tumors. We found that RAGE is present in the mitochondria of cultured tumor cells as well as primary tumors. RAGE and HMGB1 coordinately enhanced tumor cell mitochondrial complex I activity, ATP production, tumor cell proliferation and migration. Lack of RAGE or inhibition of HMGB1 release diminished ATP production and slowed tumor growth in vitro and in vivo. These findings link, for the first time, the HMGB1-RAGE pathway with changes in bioenergetics. Moreover, our observations provide a novel mechanism within the tumor microenvironment by which necrosis and inflammation promote tumor progression.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Adenosine Triphosphate / biosynthesis
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Adenosine Triphosphate / metabolism
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Animals
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Butadienes / pharmacology
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CD24 Antigen / genetics
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Cell Line, Tumor
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Cell Movement
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Cell Proliferation
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Cycloheximide / pharmacology
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Electron Transport Complex I / antagonists & inhibitors
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Electron Transport Complex I / metabolism*
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Energy Metabolism
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Enzyme Inhibitors / pharmacology
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Extracellular Signal-Regulated MAP Kinases / drug effects
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Extracellular Signal-Regulated MAP Kinases / metabolism
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HMGB1 Protein / drug effects
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HMGB1 Protein / metabolism*
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Humans
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Inflammation / metabolism
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MAP Kinase Kinase 2 / genetics
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MAP Kinase Kinase 2 / metabolism
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Mice
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Mitochondria / drug effects
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Mitochondria / metabolism
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NF-kappa B / drug effects
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NF-kappa B / metabolism
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Nitriles / pharmacology
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Pancreatic Neoplasms / metabolism
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Pancreatic Neoplasms / pathology*
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Phosphorylation / drug effects
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Protein Binding / drug effects
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Protein Synthesis Inhibitors / pharmacology
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RNA Interference
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RNA, Small Interfering / genetics
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Receptor for Advanced Glycation End Products / genetics
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Receptor for Advanced Glycation End Products / metabolism*
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Rotenone / pharmacology
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Signal Transduction
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Toll-Like Receptor 2 / genetics
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Toll-Like Receptor 4 / genetics
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Tumor Microenvironment
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Uncoupling Agents
Substances
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Butadienes
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CD24 Antigen
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Cd24a protein, mouse
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Enzyme Inhibitors
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HMGB1 Protein
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HMGB1 protein, human
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NF-kappa B
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Nitriles
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Protein Synthesis Inhibitors
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RNA, Small Interfering
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Receptor for Advanced Glycation End Products
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Tlr2 protein, mouse
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Tlr4 protein, mouse
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Toll-Like Receptor 2
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Toll-Like Receptor 4
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U 0126
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Uncoupling Agents
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Rotenone
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Adenosine Triphosphate
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Cycloheximide
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Extracellular Signal-Regulated MAP Kinases
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MAP Kinase Kinase 2
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Map2k2 protein, mouse
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Electron Transport Complex I