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 4

Metabolic impact of HADHA inhibition in OX+ LUADs.

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Metabolic impact of HADHA inhibition in OX+ LUADs. (A) Impact of glucose...
(A) Impact of glucose withdrawal on A549 (HADHA+/OX+; red) and H460 (HADHA–/OX–; blue) cell viability. (B) High-resolution respirometry comparative analysis of intact A549 and H460 cells: routine respiration (basal), leak respiration (oligomycin), ETS (uncoupled), and ROX (in presence of rotenone and antimycin A). All the parameters were corrected by ROX values. (C) Effect of trimetazidine (TMZ 500 μM; 24 hours), 5-fluorouracil (5-FU 50 μM, 24 hours), doxorubicin (DOX 5 μM; 24 hours), and etoposide (ETO 20 μM, 24 hours) on cell viability. (D) Reduction of BrdU incorporation in A549 cells treated with HADHA shRNA or with 500 μM TMZ for 24 hours in vitro. A doxycycline-induced shRNA targeting HADHA was also used to study the reversibility and the specificity of HADHA inhibition on cell proliferation after 96 hours of doxycycline washout. (E) Total cellular ATP content of A549 cells treated with saline, 500 μM TMZ for 48 hours, or doxycycline-induced shRNA-mediated HADHA knockdown. (F) Principles of the lipidomic analysis of [U-13C]-palmitate oxidative metabolism. (G) The incorporation of [U-13C]-palmitate carbons in citrate was quantified for different isotopomers (M1–M6) after 4 hours in A549 cells treated with scramble-shRNA, shRNA targeting HADHA, or 500 μM TMZ. (H) Lipidomic analysis of A549 cells treated with saline or TMZ. Differences between the treated and the untreated groups were compared using a 2-sided Student’s t test (panels A–E). For panels H and G, 1-way ANOVA with Dunnett’s correction multiple t test comparison was used. Data are expressed as mean ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.