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.
Oxidative phosphorylation induces de novo expression of the MHC class I in tumor cells through the ERK5 pathway
Charni, S.; de Bettignies, G.; Rathore, M. G.; Aguilo, J. I.; van den Elsen, P. J.; Haouzi, D.; Hipskind, R. A.; Enriquez, J. A.; Sanchez-Beato, M.; Pardo, J.; Anel, A.; Villalba, M.
2010-09-15 / vol 185 / pages 3498-503
jimmunol.1001250 [pii] 10.4049/jimmunol.1001250
1550-6606 (Electronic) 0022-1767 (Linking)
Cell Line, Tumor; Humans; Animals; Cell Proliferation; Mice; Jurkat Cells; *Oxidative Phosphorylation; Adenosine Triphosphate/biosynthesis; Cell Survival/immunology; Cell Transformation, Neoplastic/immunology/metabolism/pathology; Down-Regulation/immunology; Gene Expression Regulation/*immunology; Glutamine/metabolism; Histocompatibility Antigens Class I/*biosynthesis/genetics/metabolism; inhibitors/genetics/*physiology; Leukemia L1210; Leukemia, B-Cell/enzymology/*immunology/pathology; MAP Kinase Signaling System/genetics/*immunology; Mitogen-Activated Protein Kinase 7/antagonists &; Up-Regulation/immunology