AMOEDO, Nivea Dias; SARLAK, Saharnaz; OBRE, Emilie; ESTEVES, Pauline; BEGUERET, Hugues; KIEFFER, Yann; ROUSSEAU, Benoit; DUPIS, Alexis; IZOTTE, Julien; BELLANCE, Nadege; DARD, Laetitia; REDONNET VERNHET, Isabelle; PUNZI, Giuseppe; RODRIGUES, Mariana Figueiredo; DUMON, Elodie; MAFHOUF, Walid; GUYONNET-DUPERAT, Veronique; GALES, Lara; PALAMA, Tony; BELLVERT, Floriant; DUGOT-SENAN, Nathalie; CLAVEROL, Stephane; BASTE, Jean-Marc; LACOMBE, Didier; REZVANI, Hamid Reza; PIERRI, Ciro Leonardo; MECHTA-GRIGORIOU, Fatima; THUMEREL, Matthieu; ROSSIGNOL, Rodrigue

doi:10.1172/JCI133081

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AMOEDO, Nivea Dias
Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]

SARLAK, Saharnaz

Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]

OBRE, Emilie
Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux) [U1211 INSERM/MRGM]

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Journal of Clinical Investigation. 2021-01-04, vol. 131, n° 1

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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.< Leer menos

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

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Centros de investigación