Targeting the mitochondrial trifunctional protein restrains tumor growth in oxidative lung carcinomas

Metabolic reprogramming is a common hallmark of cancer, but a large variability in tumor bioenergetics exists between patients. Using high-resolution respirometry on fresh biopsies of human lung adenocarcinoma, we identified 2 subgroups reflected in the histologically normal, paired, cancer-adjacent...

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Bibliographic Details
Published in:The Journal of clinical investigation 2021-01, Vol.131 (1), p.1-18
Main Authors: Amoedo, Nivea Dias, Sarlak, Saharnaz, Obre, Emilie, Esteves, Pauline, Bégueret, Hugues, Kieffer, Yann, Rousseau, Benoît, Dupis, Alexis, Izotte, Julien, Bellance, Nadège, Dard, Laetitia, Redonnet-Vernhet, Isabelle, Punzi, Giuseppe, Rodrigues, Mariana Figueiredo, Dumon, Elodie, Mafhouf, Walid, Guyonnet-Dupérat, Véronique, Gales, Lara, Palama, Tony, Bellvert, Floriant, Dugot-Senan, Nathalie, Claverol, Stéphane, Baste, Jean-Marc, Lacombe, Didier, Rezvani, Hamid Reza, Pierri, Ciro Leonardo, Mechta-Grigoriou, Fatima, Thumerel, Matthieu, Rossignol, Rodrigue
Format: Article
Language:English
Subjects:
Adenocarcinoma
Bioenergetics
Biomarkers
Biomedical research
Cancer therapies
Care and treatment
Cell metabolism
Development and progression
Electron transport chain
Enzymes
Fatty acids
Gene expression
Glucose
Health aspects
Human health and pathology
Life Sciences
Lung cancer
Lung cancer, Non-small cell
Lung carcinoma
Membrane proteins
Metabolism
Mitochondria
Mitochondrial membranes
Oxidation
Phosphorylation
Physiological aspects
Proteins
Respiration
Trimetazidine
Tumors
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Summary:Metabolic reprogramming is a common hallmark of cancer, but a large variability in tumor bioenergetics exists between patients. Using high-resolution respirometry on fresh biopsies of human lung adenocarcinoma, we identified 2 subgroups reflected in the histologically normal, paired, cancer-adjacent tissue: high (OX+) mitochondrial respiration and low (OX-) mitochondrial respiration. The OX+ tumors poorly incorporated [18F]fluorodeoxy-glucose and showed increased expression of the mitochondrial trifunctional fatty acid oxidation enzyme (MTP; HADHA) compared with the paired adjacent tissue. Genetic inhibition of MTP altered OX+ tumor growth in vivo. Trimetazidine, an approved drug inhibitor of MTP used in cardiology, also reduced tumor growth and induced disruption of the physical interaction between the MTP and respiratory chain complex I, leading to a cellular redox and energy crisis. MTP expression in tumors was assessed using histology scoring methods and varied in negative correlation with [18F]fluorodeoxy-glucose incorporation. These findings provide proof-of-concept data for preclinical, precision, bioenergetic medicine in oxidative lung carcinomas.
ISSN:0021-9738
1558-8238
DOI:10.1172/JCI133081