The Oncometabolite Fumarate Promotes Pseudohypoxia Through Noncanonical Activation of NF-κB Signaling

Shanmugasundaram, Karthigayan; Nayak, B. K.; Shim, Eun Hee; Livi, Carolina B.; Block, Karen; Sudarshan, Sunil

doi:10.1074/jbc.m114.568162

Cited by 51 publications

(38 citation statements)

References 35 publications

(28 reference statements)

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“…Exposure to high levels of fumarate has been linked to genotoxic effects, as it induces DNA fragmentation and can contribute to chromosomal instability (Wentzel et al , ). Furthermore, fumarate is implicated in epigenetic regulation, EMT induction (Janin & Esteller, ; Sciacovelli et al , ), ROS production, redox homeostasis dysregulation (Shanmugasundaram et al , ), and urea cycle reversion, which have been associated with tumour growth (Collins et al , ). It also favours HIF‐1 expression and stabilization, contributing to its accumulation and to the expression of HIF‐1 target genes (Isaacs et al , ; Shanmugasundaram et al , ).…”

Section: Oncometabolites and Their Related Metabolic Enzymesmentioning

confidence: 99%

Oncometabolites in cancer aggressiveness and tumour repopulation

et al. 2019

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Tumour repopulation is recognized as a crucial event in tumour relapse where therapy-sensitive dying cancer cells influence the tumour microenvironment to sustain therapy-resistant cancer cell growth. Recent studies highlight the role of the oncometabolites succinate, fumarate, and 2-hydroxyglutarate in the aggressiveness of cancer cells and in the worsening of the patient's clinical outcome. These oncometabolites can be produced and secreted by cancer and/or surrounding cells, modifying the tumour microenvironment and sustaining an invasive neoplastic phenotype. In this review, we report recent findings concerning the role in cancer development of succinate, fumarate, and 2-hydroxyglutarate and the regulation of their related enzymes succinate dehydrogenase, fumarate hydratase, and isocitrate dehydrogenase. We propose that oncometabolites are crucially involved in tumour repopulation. The study of the mechanisms underlying the relationship between oncometabolites and tumour repopulation is fundamental for identifying efficient anti-cancer therapeutic strategies and novel serum biomarkers in order to overcome cancer relapse.

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Section: Oncometabolites and Their Related Metabolic Enzymesmentioning

confidence: 99%

Oncometabolites in cancer aggressiveness and tumour repopulation

et al. 2019

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“…Succinate also promotes an inflammatory response by Il1b activation downstream of HIF-1α stabilization (Tannahill 2013). Furthermore, fumarate levels have been linked to non-canonical NFkB activation which can accentuate hypoxia target gene activation (Shanmugasundaram 2014). It is possible that there are multiple redundant pathways that can inhibit PHDs during hypoxia including loss of substrate molecular oxygen, loss of ferrous iron cofactors, buildup of inhibiting metabolites, loss of intracellular cysteine, induction of reactive oxygen species, and potentially others.…”

Section: Chronic Hypoxic Adaptation Through Hifmentioning

confidence: 99%

Mitochondria control acute and chronic responses to hypoxia

McElroy

Chandel

2017

Experimental Cell Research

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There are numerous mechanisms by which mammals respond to hypoxia. These include acute changes in pulmonary arterial tone due to smooth muscle cell contraction, acute increases in respiration triggered by the carotid body chemosensory cells, and chronic changes such as induction of red blood cell proliferation and angiogenesis by hypoxia inducible factor targets erythropoietin and vascular endothelial growth factor, respectively. Mitochondria account for the majority of oxygen consumption in the cell and have recently been appreciated to serve as signaling organelles required for the initiation or propagation of numerous homeostatic mechanisms. Mitochondria can influence cell signaling by production of reactive oxygen species and metabolites. Here we review recent evidence that mitochondrial signals can imitate acute and chronic hypoxia responses.

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“…This results in fumarate accumulation, which, by various mechanisms, leads to the accumulation of hypoxiainducible factor (HIF), ultimately creating a pseudohypoxic state within the cell. Increased intracellular HIF levels induce the transcription of protumorigenic substances such as vascular endothelial growth factor (VEGF) and glucose transporter type 1 (GLUT-1) [ 11,12 ] . Fumarate-induced upregulation of antioxidant response element (ARE)-controlled genes may possibly also be involved in tumor development [ 13 ] .…”

Section: Discussionmentioning

confidence: 99%