Mitochondrial spare respiratory capacity: Mechanisms, regulation, and significance in non‐transformed and cancer cells

The FASEB Journal, Journal Year: 2020, Volume and Issue: 34(10), P. 13106 - 13124

Published: Aug. 17, 2020

Mitochondrial metabolism must constantly adapt to stress conditions in order maintain bioenergetic levels related cellular functions. This absence of proper adaptation can be seen a wide array conditions, including cancer. Metabolic calls on mitochondrial function and draws the reserve meet increasing needs. Among respiratory parameters, spare capacity (SRC) represents particularly robust functional parameter evaluate reserve. We provide an overview potential SRC mechanisms regulation with focus its particular significance cancer cells.

Language: Английский

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Metabolic Codependencies in the Tumor Microenvironment

Cancer Discovery, Journal Year: 2021, Volume and Issue: 11(5), P. 1067 - 1081

Published: Jan. 27, 2021

Metabolic reprogramming enables cancer cell growth, proliferation, and survival. This is driven by the combined actions of oncogenic alterations in cells host factors acting on tumor microenvironment. Cancer cell-intrinsic mechanisms activate signal transduction components that either directly enhance metabolic enzyme activity or upregulate transcription turn increase expression regulators. Extrinsic signaling involve host-derived further promote amplify cells. review describes intrinsic extrinsic driving metabolism microenvironment how such may be targeted therapeutically. SIGNIFICANCE: a consequence converging signals originating from both factors. Intrinsic maintains baseline state, whereas fine-tune processes based availability metabolites requirements Therefore, successful targeting pathways will require nuanced approach cancer's genotype, composition, tissue location.

Language: Английский

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2,4-dienoyl-CoA reductase regulates lipid homeostasis in treatment-resistant prostate cancer

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: May 19, 2020

Abstract Despite the clinical success of Androgen Receptor (AR)-targeted therapies, reactivation AR signalling remains main driver castration-resistant prostate cancer (CRPC) progression. In this study, we perform a comprehensive unbiased characterisation LNCaP cells chronically exposed to multiple inhibitors (ARI). Combined proteomics and metabolomics analyses implicate an acquired metabolic phenotype common in ARI-resistant associated with perturbed glucose lipid metabolism. To exploit phenotype, delineate subset proteins consistently ARI resistance highlight mitochondrial 2,4-dienoyl-CoA reductase (DECR1), auxiliary enzyme beta-oxidation, as clinically relevant biomarker for CRPC. Mechanistically, DECR1 participates redox homeostasis by controlling balance between saturated unsaturated phospholipids. knockout induces ER stress sensitises CRPC ferroptosis. vivo, deletion impairs metabolism reduces tumour growth, emphasizing importance development treatment resistance.

Language: Английский

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Regulation of Tumor Initiation by the Mitochondrial Pyruvate Carrier

Cell Metabolism, Journal Year: 2019, Volume and Issue: 31(2), P. 284 - 300.e7

Published: Dec. 5, 2019

Language: Английский

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Metabolic reprogramming in prostate cancer

British Journal of Cancer, Journal Year: 2021, Volume and Issue: 125(9), P. 1185 - 1196

Published: July 14, 2021

Abstract Although low risk localised prostate cancer has an excellent prognosis owing to effective treatments, such as surgery, radiation, cryosurgery and hormone therapy, metastatic remains incurable. Existing therapeutic regimens prolong life; however, they are beset by problems of resistance, resulting in poor outcomes. Treatment resistance arises primarily from tumour heterogeneity, altered genetic signatures metabolic reprogramming, all which enable the serially adapt drugs during course treatment. In this review, we focus on alterations metabolism cancer, including molecular pathways associated with reprogramming. Advances our understanding might help explain many adaptive responses that induced might, turn, lead attainment more durable responses.

Language: Английский

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Tumour metabolism and its unique properties in prostate adenocarcinoma

Nature Reviews Urology, Journal Year: 2020, Volume and Issue: 17(4), P. 214 - 231

Published: Feb. 28, 2020

Language: Английский

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Cellular and Molecular Mechanisms Underlying Prostate Cancer Development: Therapeutic Implications

Medicines, Journal Year: 2019, Volume and Issue: 6(3), P. 82 - 82

Published: July 30, 2019

Prostate cancer is the most frequent nonskin and second common cause of cancer-related deaths in man. a clinically heterogeneous disease with many patients exhibiting an aggressive progression, metastasis, other showing indolent low tendency to progression. Three stages development human prostate tumors have been identified: intraepithelial neoplasia, adenocarcinoma androgen-dependent, androgen-independent or castration-resistant. Advances molecular technologies provided very rapid progress our understanding genomic events responsible for initial progression cancer. These studies shown that genome displays relatively mutation rate compared cancers few chromosomal loss gains. The ensemble these has led suggest existence two main groups cancers: one characterized by presence ERG rearrangements (~50% harbor recurrent gene fusions involving ETS transcription factors, fusing 5′ untranslated region androgen-regulated TMPRSS2 nearly coding sequence family factor ERG) features chemoplexy (complex developing from coordinated simultaneous event), absence mutations E3 ubiquitin ligase adapter SPOP and/or deletion CDH1, chromatin remodeling factor, interchromosomal are early during development. During epigenomic abnormalities accrued converged on pathways, leading highly transcriptomic landscape, hyperactive androgen receptor signaling axis.

Language: Английский

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OXPHOS remodeling in high-grade prostate cancer involves mtDNA mutations and increased succinate oxidation

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: March 20, 2020

Abstract Rewiring of energy metabolism and adaptation mitochondria are considered to impact on prostate cancer development progression. Here, we report mitochondrial respiration, DNA mutations gene expression in paired benign/malignant human tissue samples. Results reveal reduced respiratory capacities with NADH-pathway substrates glutamate malate malignant a significant metabolic shift towards higher succinate oxidation, particularly high-grade tumors. The load potentially deleterious mitochondrial-DNA is tumors associated unfavorable risk factors. High levels Complex I-encoding genes 70% reduction capacity compensation by increased succinate-pathway capacity. Structural analyses these amino acid alterations leading effects I, supporting causal relationship. A metagene signature extracted from the transcriptome tumor samples exhibiting severe phenotype enables identification shorter survival times.

Language: Английский

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The Multifaceted Pyruvate Metabolism: Role of the Mitochondrial Pyruvate Carrier

Biomolecules, Journal Year: 2020, Volume and Issue: 10(7), P. 1068 - 1068

Published: July 17, 2020

Pyruvate, the end product of glycolysis, plays a major role in cell metabolism. Produced cytosol, it is oxidized mitochondria where fuels citric acid cycle and boosts oxidative phosphorylation. Its sole entry point into through recently identified mitochondrial pyruvate carrier (MPC). In this review, we report latest findings on physiology MPC discuss how dysfunctional can lead to diverse pathologies, including neurodegenerative diseases, metabolic disorders, cancer.

Language: Английский

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Impact of cancer metabolism on therapy resistance – Clinical implications

Drug Resistance Updates, Journal Year: 2021, Volume and Issue: 59, P. 100797 - 100797

Published: Dec. 1, 2021

Language: Английский

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