Metabolic Alterations in Cancer Cells and the Emerging Role of Oncometabolites as Drivers of Neoplastic Change

Zhou, Zhengqiu; Ibekwe, Elochukwu; Chornenkyy, Yevgen

doi:10.3390/antiox7010016

Cited by 31 publications

(33 citation statements)

References 151 publications

(175 reference statements)

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“…The term of oncometabolites refers to intermediates of metabolism that abnormally accumulate in cancer cells upstream or downstream of metabolic defects, often through loss-of-function or gain-of function mutations, respectively, in genes encoding the corresponding enzymes (177). This oncometabolites are 2-hydroxyglutarate (2HG), succinate and fumarate which have been demonstrated to contribute to the development and progression of cancer (178). The oncometabolites are produced by mutations in the nuclear-encoded TCA enzymes, isocitrate dehydrogenase 1 and 2 (IDH1/2), succinate dehydrogenase (SDH), and fumarate hydratase (FH) (177).…”

Section: Mitochondrial Oncometabolites and Mtorc1mentioning

confidence: 99%

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

et al. 2019

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Continuous proliferation of tumor cells requires constant adaptations of energy metabolism to rapidly fuel cell growth and division. This energetic adaptation often comprises deregulated glucose uptake and lactate production in the presence of oxygen, a process known as the "Warburg effect." For many years it was thought that the Warburg effect was a result of mitochondrial damage, however, unlike this proposal tumor cell mitochondria maintain their functionality, and is essential for integrating a variety of signals and adapting the metabolic activity of the tumor cell. The mammalian/mechanistic target of rapamycin complex 1 (mTORC1) is a master regulator of numerous cellular processes implicated in proliferation, metabolism, and cell growth. mTORC1 controls cellular metabolism mainly by regulating the translation and transcription of metabolic genes, such as peroxisome proliferator activated receptor γ coactivator-1 α (PGC-1α), sterol regulatory element-binding protein 1/2 (SREBP1/2), and hypoxia inducible factor-1 α (HIF-1α). Interestingly it has been shown that mTORC1 regulates mitochondrial metabolism, thus representing an important regulator in mitochondrial function. Here we present an overview on the role of mTORC1 in the regulation of mitochondrial functions in cancer, considering new evidences showing that mTORC1 regulates the translation of nucleus-encoded mitochondrial mRNAs that result in an increased ATP mitochondrial production. Moreover, we discuss the relationship between mTORC1 and glutaminolysis, as well as mitochondrial metabolites. In addition, mitochondrial fission processes regulated by mTORC1 and its impact on cancer are discussed. Finally, we also review the therapeutic efficacy of mTORC1 inhibitors in cancer treatments, considering its use in combination with other drugs, with particular focus on cellular metabolism inhibitors, that could help improve their anti neoplastic effect and eliminate cancer cells in patients. de la Cruz López et al. mTORC1 and Mitochondrial Functions Conflict of Interest: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.The handling editor declared a shared affiliation, though no other collaboration, with with several of the authors AG and KC.

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Section: Mitochondrial Oncometabolites and Mtorc1mentioning

confidence: 99%

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

et al. 2019

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“…Numerous proposals have been made regarding the possible causes for individual RMs. These largely fall into three categories: the RMs (i) provide faster ways for energy production and macromolecular biosynthesis (13); (ii) activate onco-proteins or produce oncometabolites (14); and (iii) are results of oxidative stress (15) or hypoxia (16). Although these proposals may have offered sound explanations to some RMs, there are issues that require further thinking.…”

Section: Introductionmentioning

confidence: 99%

Metabolic Reprogramming in Cancer Is Induced to Increase Proton Production

et al. 2020

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Considerable metabolic reprogramming has been observed in a conserved manner across multiple cancer types, but their true causes remain elusive. We present an analysis of around 50 such reprogrammed metabolisms (RM) including the Warburg effect, nucleotide de novo synthesis, and sialic acid biosynthesis in cancer. Analyses of the biochemical reactions conducted by these RMs, coupled with gene expression data of their catalyzing enzymes, in 7,011 tissues of 14 cancer types, revealed that all RMs produce more H þ than their original metabolisms. These data strongly support a model that these RMs are induced or selected to neutralize a persistent intracellular alkaline stress due to chronic inflammation and local iron overload. To sustain these RMs for survival, cells must find metabolic exits for the nonproton products of these RMs in a continuous manner, some of which pose major challenges, such as nucleotides and sialic acids, because they are electrically charged. This analysis strongly suggests that continuous cell division and other cancerous behaviors are ways for the affected cells to remove such products in a timely and sustained manner. As supporting evidence, this model can offer simple and natural explanations to a range of long-standing open questions in cancer research including the cause of the Warburg effect. Significance: Inhibiting acidifying metabolic reprogramming could be a novel strategy for treating cancer.

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“…In particular we discuss: How alternative splicing of pyruvate kinase M ( PKM ) gene transcripts can impact glucose catabolism by directing the choice between glycolysis and full oxidation of glucose through the Krebs cycle; The role of 2-oxoglutarate-dependent dioxygenases (2-OGDD) in controlling alternative splicing. Intermediates of the Krebs cycle influence cell features relevant to oncogenic transformation and their levels are altered by specific gene mutations ( 19 , 20 ) or in response to changes in growth conditions. These oncometabolites act by modulating the activity of 2-OGDDs that specifically target DNA, RNA, and proteins.…”

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confidence: 99%

The Krebs Cycle Connection: Reciprocal Influence Between Alternative Splicing Programs and Cell Metabolism

2018

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Alternative splicing is a pervasive mechanism that molds the transcriptome to meet cell and organism needs. However, how this layer of gene expression regulation is coordinated with other aspects of the cell metabolism is still largely undefined. Glucose is the main energy and carbon source of the cell. Not surprisingly, its metabolism is finely tuned to satisfy growth requirements and in response to nutrient availability. A number of studies have begun to unveil the connections between glucose metabolism and splicing programs. Alternative splicing modulates the ratio between M1 and M2 isoforms of pyruvate kinase in this way determining the choice between aerobic glycolysis and complete glucose oxidation in the Krebs cycle. Reciprocally, intermediates in the Krebs cycle may impact splicing programs at different levels by modulating the activity of 2-oxoglutarate-dependent oxidases. In this review we discuss the molecular mechanisms that coordinate alternative splicing programs with glucose metabolism, two aspects with profound implications in human diseases.

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Metabolic Alterations in Cancer Cells and the Emerging Role of Oncometabolites as Drivers of Neoplastic Change

Cited by 31 publications

References 151 publications

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

mTORC1 as a Regulator of Mitochondrial Functions and a Therapeutic Target in Cancer

Metabolic Reprogramming in Cancer Is Induced to Increase Proton Production

The Krebs Cycle Connection: Reciprocal Influence Between Alternative Splicing Programs and Cell Metabolism

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