Targeting the mitochondrial trifunctional protein restrains tumor growth in oxidative lung carcinomas
Nivea Dias Amoedo
(1, 2, 3)
,
Saharnaz Sarlak
(2, 3)
,
Emilie Obre
(2, 3)
,
Pauline Esteves
(2, 3)
,
Hugues Begueret
(3, 4)
,
Yann Kieffer
(5)
,
Benoit Rousseau
(2, 3)
,
Alexis Dupis
(2, 3)
,
Julien Izotte
(2, 3)
,
Nadège Bellance
(3, 2)
,
Laetitia Dard
(1, 2, 3)
,
Isabelle Redonnet-Vernhet
(1, 2, 6)
,
Giuseppe Punzi
(7)
,
Mariana Figueiredo Rodrigues
(2, 3)
,
Elodie Dumon
(2, 3)
,
Walid Mafhouf
(4, 8)
,
Véronique Guyonnet-Dupérat
(3)
,
Lara Gales
(9)
,
Tony Lionel Palama
(9)
,
Floriant Bellvert
(9)
,
Nathalie Dugot-Senan
(10)
,
Stéphane Claverol
(3, 11)
,
Jean-Marc Baste
(4)
,
Didier Lacombe
(2, 3)
,
Hamid Reza Rezvani
(3, 8)
,
Ciro Leonardo Pierri
(7)
,
Fatima Mechta-Grigoriou
(5)
,
Matthieu Thumerel
(4)
,
Rodrigue Rossignol
(1, 2, 3)
1
Cellomet [CHU Pellegrin, Bordeaux]
2 U1211 INSERM/MRGM - Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux)
3 UB - Université de Bordeaux
4 Hôpital Haut-Lévêque [CHU Bordeaux]
5 U830 - Unité de génétique et biologie des cancers
6 Hôpital Pellegrin, CHU de Bordeaux
7 UNIBA - Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro
8 Inserm U1035, Biotherapies des Maladies Genetiques et Cancers, Univ Bordeaux, CHU de Bordeaux, Pole de Biologie et Pathologie
9 TBI - Toulouse Biotechnology Institute
10 UMS3427 - INSERM US005 - TBM-Core [Bordeaux]
11 Protim - Proteomics Core Facility
2 U1211 INSERM/MRGM - Laboratoire Maladies Rares: Génétique et Métabolisme (Bordeaux)
3 UB - Université de Bordeaux
4 Hôpital Haut-Lévêque [CHU Bordeaux]
5 U830 - Unité de génétique et biologie des cancers
6 Hôpital Pellegrin, CHU de Bordeaux
7 UNIBA - Università degli studi di Bari Aldo Moro = University of Bari Aldo Moro
8 Inserm U1035, Biotherapies des Maladies Genetiques et Cancers, Univ Bordeaux, CHU de Bordeaux, Pole de Biologie et Pathologie
9 TBI - Toulouse Biotechnology Institute
10 UMS3427 - INSERM US005 - TBM-Core [Bordeaux]
11 Protim - Proteomics Core Facility
Benoit Rousseau
- Fonction : Auteur
- PersonId : 935403
Lara Gales
- Fonction : Auteur
- PersonId : 976067
- ORCID : 0000-0002-1233-2032
Tony Lionel Palama
- Fonction : Auteur
- PersonId : 173912
- IdHAL : tony-palama
- ORCID : 0000-0002-4519-4502
- IdRef : 112998070
Floriant Bellvert
- Fonction : Auteur
- PersonId : 763226
- IdHAL : floriant-bellvert
- ORCID : 0000-0002-3259-8655
Stéphane Claverol
- Fonction : Auteur
- PersonId : 760094
- ORCID : 0000-0001-5315-2823
- IdRef : 074185934
Fatima Mechta-Grigoriou
- Fonction : Auteur
- PersonId : 756038
- ORCID : 0000-0002-3751-6989
- IdRef : 09529516X
Matthieu Thumerel
- Fonction : Auteur
- PersonId : 777154
- ORCID : 0000-0003-4673-8433
Résumé
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 [F-18]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 [F-18]fluorodeoxy-glucose incorporation. These findings provide proof-of-concept data for preclinical, precision, bioenergetic medicine in oxidative lung carcinomas.