Targeting the mitochondrial trifunctional protein restrains tumor growth in oxidative lung carcinomas
Nivea Dias Amoedo, Saharnaz Sarlak, Emilie Obre, Pauline Esteves, Hugues Bégueret, Yann Kieffer, Benoît Rousseau, Alexis Dupis, Julien Izotte, Nadège Bellance, Laetitia Dard, Isabelle Redonnet-Vernhet, Giuseppe Punzi, Mariana Figueiredo Rodrigues, Elodie Dumon, Walid Mafhouf, Véronique Guyonnet-Dupérat, Lara Gales, Tony Palama, Floriant Bellvert, Nathalie Dugot-Senan, Stéphane Claverol, Jean-Marc Baste, Didier Lacombe, Hamid Reza Rezvani, Ciro Leonardo Pierri, Fatima Mechta-Grigoriou, Matthieu Thumerel, Rodrigue Rossignol
Nivea Dias Amoedo, Saharnaz Sarlak, Emilie Obre, Pauline Esteves, Hugues Bégueret, Yann Kieffer, Benoît Rousseau, Alexis Dupis, Julien Izotte, Nadège Bellance, Laetitia Dard, Isabelle Redonnet-Vernhet, Giuseppe Punzi, Mariana Figueiredo Rodrigues, Elodie Dumon, Walid Mafhouf, Véronique Guyonnet-Dupérat, Lara Gales, Tony Palama, Floriant Bellvert, Nathalie Dugot-Senan, Stéphane Claverol, Jean-Marc Baste, Didier Lacombe, Hamid Reza Rezvani, Ciro Leonardo Pierri, Fatima Mechta-Grigoriou, Matthieu Thumerel, Rodrigue Rossignol
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Research Article Metabolism Oncology

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

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.

Authors

Nivea Dias Amoedo, Saharnaz Sarlak, Emilie Obre, Pauline Esteves, Hugues Bégueret, Yann Kieffer, Benoît Rousseau, Alexis Dupis, Julien Izotte, Nadège Bellance, Laetitia Dard, Isabelle Redonnet-Vernhet, Giuseppe Punzi, Mariana Figueiredo Rodrigues, Elodie Dumon, Walid Mafhouf, Véronique Guyonnet-Dupérat, Lara Gales, Tony Palama, Floriant Bellvert, Nathalie Dugot-Senan, Stéphane Claverol, Jean-Marc Baste, Didier Lacombe, Hamid Reza Rezvani, Ciro Leonardo Pierri, Fatima Mechta-Grigoriou, Matthieu Thumerel, Rodrigue Rossignol

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Figure 2

The MTP subunit HADHA is a priority target in OX+ LUAD.

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The MTP subunit HADHA is a priority target in OX+ LUAD. (A) Volcano plot...
(A) Volcano plot of the differential label-free proteomic analysis performed between PZOX+ and HTOX+ LUADs. (B) Proteins involved in glycolysis were repressed in PZOX+, whereas proteins involved in FAO were upregulated. The mean fold change ratio between OX+ PZ and OX+ HT is indicated. (C) Analysis of HADHA expression in 586 human LUAD samples (https://www.cbioportal.org/). Tumors with a positive HADHA z score higher than 1.2 (HADHA+) are indicated in red; tumors with HADHA z score less than 0.8 (HADHA–) are shown in blue. The heatmap gives the z score for the genes listed on the left. (D) Venn diagram showing the overlap between the TCGA LUAD OX+ tumors and the TCGA LUAD HADHA+ tumors identified in panel C. (E) HADHA absolute mRNA expression in HADHA+ and HADHA– LUAD tumors. (F) RNA-Seq data from the HADHA+ and the HADHA– LUADs were analyzed using DESeq2 to generate the list of genes that differed between the 2 groups (adjusted P < 0.005). This list was further analyzed using Metascape (metascape.org) to identify all statistically enriched GO/KEGG terms. The significant terms were then hierarchically clustered into a tree and converted into a network layout. Each term is represented by a circle node, where its size is proportional to the number of genes, and its color represents its cluster. Terms with a similarity score higher than 0.3 are linked by an edge (the thickness represents the similarity score) and visualized with Cytoscape (v3.1.2). One term from each cluster was selected as label. (G) Genes coexpressed with HADHA in TCGA lung tumors. The top genes with a Pearson coefficient higher than 0.35 are shown in the bar graph. Data are expressed as mean ± SEM.