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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.

SUBMITTER: Amoedo ND

PROVIDER: S-EPMC7773363 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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

Amoedo Nivea Dias ND Sarlak Saharnaz S Obre Emilie E Esteves Pauline P Bégueret Hugues H Kieffer Yann Y Rousseau Benoît B Dupis Alexis A Izotte Julien J Bellance Nadège N Dard Laetitia L Redonnet-Vernhet Isabelle I Punzi Giuseppe G Rodrigues Mariana Figueiredo MF Dumon Elodie E Mafhouf Walid W Guyonnet-Dupérat Véronique V Gales Lara L Palama Tony T Bellvert Floriant F Dugot-Senan Nathalie N Claverol Stéphane S Baste Jean-Marc JM Lacombe Didier D Rezvani Hamid Reza HR Pierri Ciro Leonardo CL Mechta-Grigoriou Fatima F Thumerel Matthieu M Rossignol Rodrigue R

The Journal of clinical investigation 20210101 1

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 ...[more]

PMID: 33393495

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Project description:BackgroundMastic oil from Pistacia lentiscus variation chia, a blend of bioactive terpenes with recognized medicinal properties, has been recently shown to exert anti-tumor growth activity through inhibition of cancer cell proliferation, survival, angiogenesis and inflammatory response. However, no studies have addressed its mechanisms of action at genome-wide gene expression level.MethodsTo investigate molecular mechanisms triggered by mastic oil, Lewis Lung Carcinoma cells were treated with mastic oil or DMSO and RNA was collected at five distinct time points (3-48 h). Microarray expression profiling was performed using Illumina mouse-6 v1 beadchips, followed by computational analysis. For a number of selected genes, RT-PCR validation was performed in LLC cells as well as in three human cancer cell lines of different origin (A549, HCT116, K562). PTEN specific inhibition by a bisperovanadium compound was applied to validate its contribution to mastic oil-mediated anti-tumor growth effects.ResultsIn this work we demonstrated that exposure of Lewis lung carcinomas to mastic oil caused a time-dependent alteration in the expression of 925 genes. GO analysis associated expression profiles with several biological processes and functions. Among them, modifications on cell cycle/proliferation, survival and NF-kappaB cascade in conjunction with concomitant regulation of genes encoding for PTEN, E2F7, HMOX1 (up-regulation) and NOD1 (down-regulation) indicated some important mechanistic links underlying the anti-proliferative, pro-apoptotic and anti-inflammatory effects of mastic oil. The expression profiles of Hmox1, Pten and E2f7 genes were similarly altered by mastic oil in the majority of test cancer cell lines. Inhibition of PTEN partially reversed mastic oil effects on tumor cell growth, indicating a multi-target mechanism of action. Finally, k-means clustering, organized the significant gene list in eight clusters demonstrating a similar expression profile. Promoter analysis in a representative cluster revealed shared putative cis-elements suggesting a common regulatory transcription mechanism.ConclusionsPresent results provide novel evidence on the molecular basis of tumor growth inhibition mediated by mastic oil and set a rational basis for application of genomics and bioinformatic methodologies in the screening of natural compounds with potential cancer chemopreventive activities.

Dataset Information

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

Publications

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

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