Metabolite sensing and signaling in cancer

Wang, Yiping; Li, Jintao; Qu, Jia; Yin, Miao; Lei, Qun-Ying

doi:10.1074/jbc.rev119.007624

Cited by 58 publications

(40 citation statements)

References 66 publications

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“…Indeed, mutant IDH1 or IDH2 lose their canonical function for converting isocitrate to α-ketoglutarate (α-KG), acquiring the neomorphic activity to catalyze the production of 2-HG [76]. This oncometabolite is structurally similar to α-KG; thereby, it competitively inhibits α-KG-dependent enzymes, deregulating the TCA cycle and inducing histone-and DNA-hypermethylation inhibition of epigenetic regulators [77,78]. The final consequence of 2-HG over-production in IDH-mutant AML is impaired cellular growth and differentiation arrest [79,80].…”

Section: Effects Of Altered Metabolism On Epigenetic Regulationmentioning

confidence: 99%

The Role of Hypoxic Bone Marrow Microenvironment in Acute Myeloid Leukemia and Future Therapeutic Opportunities

Bruno

Mancini

Santis

et al. 2021

IJMS

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Acute myeloid leukemia (AML) is a hematologic malignancy caused by a wide range of alterations responsible for a high grade of heterogeneity among patients. Several studies have demonstrated that the hypoxic bone marrow microenvironment (BMM) plays a crucial role in AML pathogenesis and therapy response. This review article summarizes the current literature regarding the effects of the dynamic crosstalk between leukemic stem cells (LSCs) and hypoxic BMM. The interaction between LSCs and hypoxic BMM regulates fundamental cell fate decisions, including survival, self-renewal, and proliferation capacity as a consequence of genetic, transcriptional, and metabolic adaptation of LSCs mediated by hypoxia-inducible factors (HIFs). HIF-1α and some of their targets have been associated with poor prognosis in AML. It has been demonstrated that the hypoxic BMM creates a protective niche that mediates resistance to therapy. Therefore, we also highlight how hypoxia hallmarks might be targeted in the future to hit the leukemic population to improve AML patient outcomes.

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Section: Effects Of Altered Metabolism On Epigenetic Regulationmentioning

confidence: 99%

The Role of Hypoxic Bone Marrow Microenvironment in Acute Myeloid Leukemia and Future Therapeutic Opportunities

Bruno

Mancini

Santis

et al. 2021

IJMS

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“…It is now recognized that cancer metabolism goes well beyond simple tumor proliferation and survival with the identification and characterization of the so-called “oncometabolites”, whose abnormal and chronic accumulation through cancer-related mutations in cellular metabolism genes can drive transformation to malignancy [ 4 , 5 ]. In this regard, metabolic profiling has great potential to guide diagnostics and treatments by unearthing novel biomarkers of disease and therapeutic targets [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Succinate Pathway in Head and Neck Squamous Cell Carcinoma: Potential as a Diagnostic and Prognostic Marker

Terra

Ceperuelo-Mallafré

Merma

et al. 2021

Cancers

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Head and neck squamous cell carcinoma (HNSCC) is characterized by high rates of mortality and treatment-related morbidity, underscoring the urgent need for innovative and safe treatment strategies and diagnosis practices. Mitochondrial dysfunction is a hallmark of cancer and can lead to the accumulation of tricarboxylic acid cycle intermediates, such as succinate, which function as oncometabolites. In addition to its role in cancer development through epigenetic events, succinate is an extracellular signal transducer that modulates immune response, angiogenesis and cell invasion by activating its cognate receptor SUCNR1. Here, we explored the potential value of the circulating succinate and related genes in HNSCC diagnosis and prognosis. We determined the succinate levels in the serum of 66 pathologically confirmed, untreated patients with HNSCC and 20 healthy controls. We also surveyed the expression of the genes related to succinate metabolism and signaling in tumoral and nontumoral adjacent tissue and in normal mucosa from 50 patients. Finally, we performed immunohistochemical analysis of SUCNR1 in mucosal samples. The results showed that the circulating levels of succinate were higher in patients with HNSCC than in the healthy controls. Additionally, the expression of SUCNR1, HIF-1α, succinate dehydrogenase (SDH) A, and SDHB was higher in the tumor tissue than in the matched normal mucosa. Consistent with this, immunohistochemical analysis revealed an increase in SUCNR1 protein expression in tumoral and nontumoral adjacent tissue. High SUCNR1 and SDHA expression levels were associated with poor locoregional control, and the locoregional recurrence-free survival rate was significantly lower in patients with high SUCNR1 and SDHA expression than in their peers with lower levels (77.1% [95% CI: 48.9–100.0] vs. 16.7% [95% CI: 0.0–44.4], p = 0.018). Thus, the circulating succinate levels are elevated in HNSCC and high SUCNR1/SDHA expression predicts poor locoregional disease-free survival, identifying this oncometabolite as a potentially valuable noninvasive biomarker for HNSCC diagnosis and prognosis.

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“…Redox status of the cell and the availability of nutrients are of prime importance to determine the actual cell fate. The impressive diversity of sugar signaling events and its connections with other cellular indicators have been reviewed recently for plants (105), and also for mammalian cells (191). In general, common principles are playing crucial roles in all organisms.…”

Section: Small Molecules Fine-tune the Redox Switchesmentioning

confidence: 99%

Central Metabolism in Mammals and Plants as a Hub for Controlling Cell Fate

Selinski

Scheibe

2021

Antioxidants & Redox Signaling

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Significance: The importance of oxidoreductases in energy metabolism together with the occurrence of enzymes of central metabolism in the nucleus gave rise to the active research field aiming to understand moonlighting enzymes that undergo post-translational modifications (PTMs) before carrying out new tasks. Recent Advances: Cytosolic enzymes were shown to induce gene transcription after PTM and concomitant translocation to the nucleus. Changed properties of the oxidized forms of cytosolic glyceraldehyde 3-phosphate dehydrogenase, and also malate dehydrogenases and others, are the basis for a hypothesis suggesting moonlighting functions that directly link energy metabolism to adaptive responses required for maintenance of redox-homeostasis in all eukaryotes. Critical Issues: Small molecules, such as metabolic intermediates, coenzymes, or reduced glutathione, were shown to fine-tune the redox switches, interlinking redox state, metabolism, and induction of new functions via nuclear gene expression. The cytosol with its metabolic enzymes connecting energy fluxes between the various cell compartments can be seen as a hub for redox signaling, integrating the different signals for graded and directed responses in stressful situations. Future Directions: Enzymes of central metabolism were shown to interact with p53 or the assumed plant homologue suppressor of gamma response 1 (SOG1), an NAM, ATAF, and CUC transcription factor involved in the stress response upon ultraviolet exposure. Metabolic enzymes serve as sensors for imbalances, their inhibition leading to changed energy metabolism, and the adoption of transcriptional coactivator activities. Depending on the intensity of the impact, rerouting of energy metabolism, proliferation, DNA repair, cell cycle arrest, immune responses, or cell death will be induced. Antioxid. Redox Signal. 34, 1025–1047.

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Metabolite sensing and signaling in cancer

Cited by 58 publications

References 66 publications

The Role of Hypoxic Bone Marrow Microenvironment in Acute Myeloid Leukemia and Future Therapeutic Opportunities

The Role of Hypoxic Bone Marrow Microenvironment in Acute Myeloid Leukemia and Future Therapeutic Opportunities

Succinate Pathway in Head and Neck Squamous Cell Carcinoma: Potential as a Diagnostic and Prognostic Marker

Central Metabolism in Mammals and Plants as a Hub for Controlling Cell Fate

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