2-Hydroxyglutarate in Cancer Cells

Abstract

Significance: Cancer cells are stabilized in an undifferentiated state similar to stem cells. This leads to profound modifications of their metabolism, which further modifies their genetics and epigenetics as malignancy progresses. Specific metabolites and enzymes may serve as clinical markers of cancer progression. Recent Advances: Both 2-hydroxyglutarate (2HG) enantiomers are associated with reprogrammed metabolism, in grade III/IV glioma, glioblastoma, and acute myeloid leukemia cells, and numerous other cancer types, while acting also in the cross talk of tumors with immune cells. 2HG contributes to specific alternations in cancer metabolism and developed oxidative stress, while also inducing decisions on the differentiation of naive T lymphocytes, and serves as a signal messenger in immune cells. Moreover, 2HG inhibits chromatin-modifying enzymes, namely 2-oxoglutarate-dependent dioxygenases, and interferes with hypoxia-inducible factor (HIF) transcriptome reprogramming and mammalian target of rapamycin (mTOR) pathway, thus dysregulating gene expression and further promoting cancerogenesis. Critical Issues: Typically, heterozygous mutations within the active sites of isocitrate dehydrogenase isoform 1 (IDH1) R132H and mitochondrial isocitrate dehydrogenase isoform 2 (IDH2) R140Q provide cells with millimolar r-2-hydroxyglutarate (r-2HG) concentrations, whereas side activities of lactate and malate dehydrogenase form submillimolar s-2-hydroxyglutarate (s-2HG). However, even wild-type IDH1 and IDH2, notably under shifts toward reductive carboxylation glutaminolysis or changes in other enzymes, lead to ''intermediate'' 0.01-0.1 mM 2HG levels, for example, in breast carcinoma compared with 10-8 M in noncancer cells. Future Directions: Uncovering further molecular metabolism details specific for given cancer cell types and sequence-specific epigenetic alternations will lead to the design of diagnostic approaches, not only for predicting patients' prognosis or uncovering metastases and tumor remissions but also for early diagnostics. Antioxid. Redox Signal. 00, 000-000.

Epigenetic crosstalk between hypoxia and tumor driven by HIF regulation

“…Isocitrate dehydrogenase isoform-1 (IDH1) and 2 (IDH2) mutations are considered to be associated with HIF-α stability in solid tumors, notably glioblastoma and acute myeloid leukemia (AML) [ 166 , 167 ]. Mutant IDH proteins obtain neomorphic enzymatic activity that catalyze the transformation of α-ketoglutarate (α-KG) to R-2-hydroxyglutarate (R-2HG), which activates prolyl hydroxylase domain-2 that further leads to the degradation of HIF-α [ 168 ]. Moreover, non-catalytic enzymes associated with metabolic plasticity could also interact with HIF-α, such as fructose-1,6-bisphosphatase (FBP1) and PKM2.…”

The Mitochondrial Citrate Carrier SLC25A1/CIC and the Fundamental Role of Citrate in Cancer, Inflammation and Beyond

“…Wild-type IDH1 and IDH2 have been reported to produce low levels of 2-HGs under reductive carboxylation conditions [ 73 ], raising the possibility that this mechanism comes into play in these disorders. Alternative sources of 2-HGs are the promiscuous activities of malate or lactate dehydrogenase (MDH1/2 and LDH, respectively), impaired activity of L2- or D2-HGDHs due to excess substrate(s) or altered redox balance [ 69 , 74 , 75 ]. Reduced concentrations of malate and increased levels of NADH, hypoxia or metabolic acidosis due to enhanced lactic acid concentrations can all favor the promiscuous activity of MDH2 or LDH [ 73 ].…”

Mitochondrial Dysfunction in Age‐Related Metabolic Disorders

“…. [104] S-glutathionylation inhibits UCP2 and UCP3-dependent uncoupling, in turn enhancing glucose-stimulated insulin secretion. [105] Similarly, inhibition of UCP2 by genipin (a protein cross-linking agent) has a negative impact on the yield of ATP from glucose.…”