학술논문
Targeting the mitochondrial trifunctional protein restrains tumor growth in oxidative lung carcinomas.
Document Type
Journal Article
Author
Amoedo, Nivea Dias; Sarlak, Saharnaz; Obre, Emilie; Esteves, Pauline; Bégueret, Hugues; Kieffer, Yann; Rousseau, Benoît; Dupis, Alexis; Izotte, Julien; Bellance, NadÃge; Dard, Laetitia; Redonnet-Vernhet, Isabelle; Punzi, Giuseppe; Rodrigues, Mariana Figueiredo; Dumon, Elodie; Mafhouf, Walid; Guyonnet-Dupérat, Véronique; Gales, Lara; Palama, Tony; Bellvert, Floriant
Source
Subject
*TUMOR growth
*MITOCHONDRIAL proteins
*TUMOR proteins
*FATTY acid oxidation
*LUNGS
*MITOCHONDRIAL pathology
*PROTEIN metabolism
*PROTEINS
*DRUG delivery systems
*RESEARCH
*HETEROCYCLIC compounds
*RESEARCH methodology
*LUNG tumors
*MEDICAL cooperation
*EVALUATION research
*COMPARATIVE studies
*CELL lines
*OXIDATION-reduction reaction
*CHEMICAL inhibitors
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Language
ISSN
0021-9738
Abstract
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. [ABSTRACT FROM AUTHOR]