Targeting the mitochondrial trifunctional protein restrains tumor growth in oxidative lung carcinomas
Nivea Dias Amoedo, … , Matthieu Thumerel, Rodrigue Rossignol
Nivea Dias Amoedo, … , Matthieu Thumerel, Rodrigue Rossignol
Published January 4, 2021
Citation Information: J Clin Invest. 2021;131(1):e133081. https://doi.org/10.1172/JCI133081.
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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 3

HADHA+ LUAD tumor and cell line stratification.

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HADHA+ LUAD tumor and cell line stratification. (A) HADHA immunohistolog...
(A) HADHA immunohistology staining in mouse heart (40× zoom). A strong HADHA cytosolic staining (brown) can be observed in the myofibers (nuclei were stained in blue). (B) This method was applied to study HADHA expression in paraffin-embedded sections of lung tumors stained with hematoxylin (blue), eosin (red), and with a monoclonal antibody recognizing HADHA (brown staining). Representative tumors with either high HADHA expression (HADHA+ LUAD; left panel) or low HADHA expression (HADHA– LUAD; right panel) are shown. (C) HADHA tissue expression in the tumor and the noncancer tissue was used to calculate the HADHA histology score in 32 tumor samples. Tumors with HADHA score greater than median absolute deviation (MAD) were denominated HADHA+ LUADs (shown in red) and tumors with HADHA score less than MAD were denoted HADHA– LUADs (shown in blue). (D) Distribution of the [18F]-FDG–PET scan SUVmax values. (E) HADHA expression was determined by Western blot on a panel of 12 human lung cancer cell lines. (F) HADHA expression normalized to actin levels (mean expression value at dashed line) was used to segregate the cell lines with high (HADHA+; red) or low HADHA expression (HADHA–; blue). Cells with a black symbol show no difference to the median value. (G) Mitochondrial respiration was measured in the 12 human lung cancer cell lines using the Seahorse extracellular flux analyzer. The mean (dashed line) was used to segregate the cell lines with high (red) or low (blue) respiration. Cells with a plain symbol correspond to the HADHA–/OX– group (plain blue) or to the HADHA+/OX+ group (plain red). Data are expressed as mean ± SEM. **P < 0.01.