Abstract
Most cancer cells use anaerobic-like glycolysis to generate energy instead of oxidative phosphorylation. They also avoid recognition by CTLs, which occurs primarily through decreasing the level of MHC class I (MHC-I) at the cell surface. We find that the two phenomena are linked; culture conditions that force respiration in leukemia cells upregulate MHC-I transcription and protein levels at the cell surface, whereas these decrease in cells forced to perform fermentation as well as in leukemia cells lacking a functional mitochondrial respiratory chain. Forced respiration leads to increased expression of the MAPK ERK5, which activates MHC-I gene promoters, and ERK5 accumulation in mitochondria. Respiration-induced MHC-I upregulation is reversed upon short hairpin RNA-mediated ERK5 downregulation and by inactive mutants of ERK5. Moreover, short hairpin RNA for ERK5 leukemia cells do not tolerate forced respiration. Thus, the expression of ERK5 and MHC-I is linked to cell metabolism and notably diminished by the metabolic adaptations found in tumor cells.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / biosynthesis
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Animals
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Cell Line, Tumor
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Cell Proliferation
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Cell Survival / immunology
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Cell Transformation, Neoplastic / immunology
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Cell Transformation, Neoplastic / metabolism
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Cell Transformation, Neoplastic / pathology
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Down-Regulation / immunology
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Gene Expression Regulation / immunology*
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Glutamine / metabolism
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Histocompatibility Antigens Class I / biosynthesis*
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Histocompatibility Antigens Class I / genetics
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Histocompatibility Antigens Class I / metabolism
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Humans
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Jurkat Cells
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Leukemia L1210
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Leukemia, B-Cell / enzymology
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Leukemia, B-Cell / immunology*
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Leukemia, B-Cell / pathology
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MAP Kinase Signaling System / genetics
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MAP Kinase Signaling System / immunology*
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Mice
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Mitogen-Activated Protein Kinase 7 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 7 / genetics
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Mitogen-Activated Protein Kinase 7 / physiology*
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Oxidative Phosphorylation*
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Up-Regulation / immunology
Substances
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Histocompatibility Antigens Class I
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Glutamine
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Adenosine Triphosphate
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Mitogen-Activated Protein Kinase 7