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

Amoêdo, Nívea Dias; Sarlak, Saharnaz; Obre, Émilie; Esteves, Pauline; Bégueret, Hugues; Kieffer, Yann; Rousseau, Benoı̂t; Alexis, Dupis; Izotte, Julien; Bellancé, Nadège; Dard, Laetitia; Redonnet‐Vernhet, Isabelle; Punzi, Giuseppe; Rodrigues, M; Dumon, Elodie; Mafhouf, Walid; Guyonnet‐Duperat, Véronique; Gales, Lara; Palama, Tony; Bellvert, Floriant; Dugot-Senan, Nathalie; Claverol, Stéphane; Baste, Jean-Marc; Lacombe, Didier; Rezvani, Hamid Reza; Pierri, Ciro Leonardo; Mechta‐Grigoriou, Fatima; Thumerel, Matthieu; Rossignol, Rodrigue

doi:10.1172/jci133081

Cited by 30 publications

(31 citation statements)

References 62 publications

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“…Most likely, these are cancers that have been shown to be oxidative. Amoedo et al identified two subgroups of lung carcinomas—high and low OXPHOS-expressing tumors [ 62 ]. The high OXPHOS-expressing tumors poorly incorporated fluorodeoxyglucose (18F) and had increased expression of the mitochondrial trifunctional fatty acid oxidation enzyme (TFP; particularly TFP subunit alpha) compared to the paired adjacent tissue.…”

Section: The Importance Of Fas and Mfao For Cancer Cellsmentioning

confidence: 99%

A “Weird” Mitochondrial Fatty Acid Oxidation as a Metabolic “Secret” of Cancer

Zhelev

Aoki

Lazarova

et al. 2022

Oxidative Medicine and Cellular Longevity

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Cancer metabolism is an extensively studied field since the discovery of the Warburg effect about 100 years ago and continues to be increasingly intriguing and enigmatic so far. It has become clear that glycolysis is not the only abnormally activated metabolic pathway in the cancer cells, but the same is true for the fatty acid synthesis (FAS) and mevalonate pathway. In the last decade, a lot of data have been accumulated on the pronounced mitochondrial fatty acid oxidation (mFAO) in many types of cancer cells. In this article, we discuss how mFAO can escape normal regulation under certain conditions and be overactivated. Such abnormal activation of mitochondrial β-oxidation can also be combined with mutations in certain enzymes of the Krebs cycle that are common in cancer. If overactivated β-oxidation is combined with other common cancer conditions, such as dysfunctions in the electron transport complexes, and/or hypoxia, this may alter the redox state of the mitochondrial matrix. We propose the idea that the altered mitochondrial redox state and/or inhibited Krebs cycle at certain segments may link mitochondrial β-oxidation to the citrate-malate shuttle instead to the Krebs cycle. We call this abnormal metabolic condition “β-oxidation shuttle”. It is unconventional mFAO, a separate metabolic pathway, unexplored so far as a source of energy, as well as a source of cataplerosis, leading to biomass accumulation, accelerated oxygen consumption, and ultimately a source of proliferation. It is inefficient as an energy source and must consume significantly more oxygen per mole of ATP produced when combined with acetyl-CoA consuming pathways, such as the FAS and mevalonate pathway.

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Section: The Importance Of Fas and Mfao For Cancer Cellsmentioning

confidence: 99%

A “Weird” Mitochondrial Fatty Acid Oxidation as a Metabolic “Secret” of Cancer

Zhelev

Aoki

Lazarova

et al. 2022

Oxidative Medicine and Cellular Longevity

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“…Sample preparation and protein digestion, nLC-MS/MS analysis, and database search and results processing were performed as described in [ 19 ].…”

Section: Methodsmentioning

confidence: 99%

“…In particular, the bioinformatic study of proteome changes could allow for prediction of the putative transcription factors, kinases or microRNAs involved in the observed changes based on the detailed knowledge of their targets and directionality of the expected changes in target expression. We recently used this predictive strategy to discover the role of various genetic regulators in different disease contexts [ 16 , 17 , 18 , 19 ]. Of note, a clearer understanding of the molecular basis of diabetic nephropathy was obtained using large-scale characterization proteomics, and innovative therapeutic approaches can be derived from this knowledge [ 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

Proteomic Study of Low-Birth-Weight Nephropathy in Rats

Imasawa

Claverol

Lacombe

et al. 2021

IJMS

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The hyperfiltration theory has been used to explain the mechanism of low birth weight (LBW)-related nephropathy. However, the molecular changes in the kidney proteome have not been defined in this disease, and early biomarkers are lacking. We investigated the molecular pathogenesis of LBW rats obtained by intraperitoneal injection of dexamethasone into pregnant animals. Normal-birth-weight (NBW) rats were used as controls. When the rats were four weeks old, the left kidneys were removed and used for comprehensive label-free proteomic studies. Following uninephrectomy, all rats were fed a high-salt diet until 9 weeks of age. Differences in the molecular composition of the kidney cortex were observed at the early step of LBW nephropathy pathogenesis. Untargeted quantitative proteomics showed that proteins involved in energy metabolism, such as oxidative phosphorylation (OXPHOS), the TCA cycle, and glycolysis, were specifically downregulated in the kidneys of LBW rats at four weeks. No pathological changes were detected at this early stage. Pathway analysis identified NEFL2 (NRF2) and RICTOR as potential upstream regulators. The search for biomarkers identified components of the mitochondrial respiratory chain, namely, ubiquinol-cytochrome c reductase complex subunits (UQCR7/11) and ATP5I/L, two components of mitochondrial F1FO-ATP synthase. These findings were further validated by immunohistology. At later stages of the disease process, the right kidneys revealed an increased frequency of focal segmental glomerulosclerosis lesions, interstitial fibrosis and tubular atrophy. Our findings revealed proteome changes in LBW rat kidneys and revealed a strong downregulation of specific mitochondrial respiratory chain proteins, such as UQCR7.

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“…Since the 1920s, when Otto Warburg highlighted an increase in aerobic glycolytic activity in cancer cells, different discoveries have shown that tumor metabolism is a complex network of rewiring biochemical reactions allowing the anabolic growth of cancer cells by the conversion of nutrients into metabolites [ 2 , 3 , 4 ]. Nutrients such as glucose, amino acids or fatty acids are metabolized through glycolysis and/or the tricarboxylic acid (TCA) cycle to be converted into adenosine triphosphate (ATP), proteins, lipids and lactate to support the energy and “building block” demands of highly proliferative cells [ 4 , 5 , 6 ]. Aberrant mutations enable tumor cells to acquire this metabolic state, and the most studied aberrant mutations belong to the myelocytomatosis oncogene (MYC) and phosphoinositide 3-kinase (PI3K)–protein kinase B (Akt)–mammalian target of rapamycin (mTOR) signaling pathways.…”

Section: Introductionmentioning

confidence: 99%

Targeting Metabolism to Control Immune Responses in Cancer and Improve Checkpoint Blockade Immunotherapy

Luby

Alves-Guerra

2021

Cancers

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Over the past decade, advances in cancer immunotherapy through PD1–PDL1 and CTLA4 immune checkpoint blockade have revolutionized the management of cancer treatment. However, these treatments are inefficient for many cancers, and unfortunately, few patients respond to these treatments. Indeed, altered metabolic pathways in the tumor play a pivotal role in tumor growth and immune response. Thus, the immunosuppressive tumor microenvironment (TME) reprograms the behavior of immune cells by altering their cellular machinery and nutrient availability to limit antitumor functions. Today, thanks to a better understanding of cancer metabolism, immunometabolism and immune checkpoint evasion, the development of new therapeutic approaches targeting the energy metabolism of cancer or immune cells greatly improve the efficacy of immunotherapy in different cancer models. Herein, we highlight the changes in metabolic pathways that regulate the differentiation of pro- and antitumor immune cells and how TME-induced metabolic stress impedes their antitumor activity. Finally, we propose some drug strategies to target these pathways in the context of cancer immunotherapy.

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

Cited by 30 publications

References 62 publications

A “Weird” Mitochondrial Fatty Acid Oxidation as a Metabolic “Secret” of Cancer

A “Weird” Mitochondrial Fatty Acid Oxidation as a Metabolic “Secret” of Cancer

Proteomic Study of Low-Birth-Weight Nephropathy in Rats

Targeting Metabolism to Control Immune Responses in Cancer and Improve Checkpoint Blockade Immunotherapy

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