Oxidative phosphorylation induces de novo expression of the MHC class I in tumor cells through the ERK5 pathway.
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.
Charni
Seyma
S
Institut de Génétique Moléculaire de Montpellier, Unité Mixte de Recherche 5535, Centre National de Recherche Scientifique, Montpellier, France.
de Bettignies
Geoffroy
G
Rathore
Moeez G
MG
Aguiló
Juan I
JI
van den Elsen
Peter J
PJ
Haouzi
Delphine
D
Hipskind
Robert A
RA
Enriquez
José Antonio
JA
Sanchez-Beato
Margarita
M
Pardo
Julián
J
Anel
Alberto
A
Villalba
Martin
M
D000255:Adenosine Triphosphate / Q000096:biosynthesis; D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000276:immunology; D002471:Cell Transformation, Neoplastic / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D015536:Down-Regulation / Q000276:immunology; D005786:Gene Expression Regulation / Q000276:immunology*; D005973:Glutamine / Q000378:metabolism; D015395:Histocompatibility Antigens Class I / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D007939:Leukemia L1210; D015448:Leukemia, B-Cell / Q000201:enzymology / Q000276:immunology* / Q000473:pathology; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology*; D051379:Mice; D048054:Mitogen-Activated Protein Kinase 7 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D010085:Oxidative Phosphorylation; D015854:Up-Regulation / Q000276:immunology
D015395:Histocompatibility Antigens Class I; D005973:Glutamine; D000255:Adenosine Triphosphate; D048054:Mitogen-Activated Protein Kinase 7