bims-glucam 2022-12-11 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2022‒12‒11
seven papers selected by
Sreeparna Banerjee
Middle East Technical University

Glutamine metabolism and radiosensitivity: Beyond the Warburg effect.
Circ_0000069 contributes to the growth, metastasis and glutamine metabolism in renal cell carcinoma (RCC) via regulating miR-125a-5p-dependent SLC1A5 expression.
Bioinspired nanocatalytic tumor therapy by simultaneous reactive oxygen species generation enhancement and glutamine pathway-mediated glutathione depletion.
Establishing a glutamine metabolism-based model for predicting the prognosis of low-grade glioma.
Ribitol alters multiple metabolic pathways of central carbon metabolism with enhanced glycolysis: A metabolomics and transcriptomics profiling of breast cancer.
The impact of the microbiome in cancer: Targeting metabolism of cancer cells and host.
Nitric oxide regulation of cellular metabolism: Adaptive tuning of cellular energy.

Front Oncol. 2022 ;12 1070514

Glutamine metabolism and radiosensitivity: Beyond the Warburg effect.

Ryan S Alden, Mohammad Zahid Kamran, Bassel A Bashjawish, Brittany A Simone.

  Mounting data suggest that cancer cell metabolism can be utilized therapeutically to halt cell proliferation, metastasis and disease progression. Radiation therapy is a critical component of cancer treatment in curative and palliative settings. The use of metabolism-based therapeutics has become increasingly popular in combination with radiotherapy to overcome radioresistance. Over the past year, a focus on glutamine metabolism in the setting of cancer therapy has emerged. In this mini-review, we discuss several important ways (DNA damage repair, oxidative stress, epigenetic modification and immune modulation) glutamine metabolism drives cancer growth and progression, and present data that inhibition of glutamine utilization can lead to radiosensitization in preclinical models. Future research is needed in the clinical realm to determine whether glutamine antagonism is a feasible synergistic therapy that can be combined with radiotherapy.

Keywords:  cancer; glutamine (Gln); immunotherapy; metabolism; radiation; radiosensitivity; sirpiglenastat; telaglenastat

DOI:  https://doi.org/10.3389/fonc.2022.1070514
Transpl Immunol. 2022 Nov 30. pii: S0966-3274(22)00238-6. [Epub ahead of print] 101764

Circ_0000069 contributes to the growth, metastasis and glutamine metabolism in renal cell carcinoma (RCC) via regulating miR-125a-5p-dependent SLC1A5 expression.

Liqing Yang, Lin Wang, Jitao Wu, Yongqiang Wang.

  BACKGROUND: Circular RNAs (circRNAs) have emerged as critical mediators in various cancers, including renal cell carcinoma (RCC). In the present research, the functions of circ_0000069 in RCC were explored.METHODS: Quantitative real-time polymerase chain reaction (qRT-PCR) assay, western blot assay and immunohistochemistry (IHC) assay were performed for the expression of circ_0000069, microRNA-125a-5p (miR-125a-5p) and solute carrier family 1 member 5 (SLC1A5). Cell Counting Kit-8 (CCK-8) assay and 5'-ethynyl-2'-deoxyuridine (EdU) assay were performed for cell proliferation. Flow cytometry assay was manipulated for cell apoptosis. Transwell assay and wound-healing assay were utilized for cell invasion and migration. Glutamine metabolism level was evaluated by examining glutamine consumption, α-ketoglutarate production and glutamate production. Dual-luciferase reporter assay was used to analyze the relationships of circ_0000069, miR-125a-5p and SLC1A5. Murine xenograft model assay was conducted to analyze the function of circ_0000069 in vivo.
RESULTS: Circ_0000069 level was abnormally upregulated in RCC tissues and cells. Knockdown of circ_0000069 inhibited the proliferation, invasion, migration and glutamine metabolism and promoted the apoptosis in RCC cells in vitro and restrained tumor growth in vivo. Circ_0000069 served as the sponge for miR-125a-5p. MiR-125a-5p inhibition ameliorated the effects of circ_0000069 knockdown on RCC cell malignant behaviors. SLC1A5 was identified as the target gene of miR-125a-5p. Moreover, miR-125a-5p overexpression repressed the progression of RCC cells, while SLC1A5 elevation abrogated the effect.
CONCLUSION: Circ_0000069 knockdown inhibited the carcinogenesis of RCC by regulating miR-125a-5p/SLC1A5 axis.

Keywords:  Renal cell carcinoma; SLC1A5; circ_0000069; miR-125a-5p

DOI:  https://doi.org/10.1016/j.trim.2022.101764
J Mater Chem B. 2022 Dec 09.

Bioinspired nanocatalytic tumor therapy by simultaneous reactive oxygen species generation enhancement and glutamine pathway-mediated glutathione depletion.

Huijia Mao, Yangyang Wen, Yonghui Yu, Hongyan Li, Jing Wang, Baoguo Sun.

An insufficient intracellular H2O2 level and overexpressed glutathione (GSH) are still the major challenges for effective chemodynamic therapy (CDT). Inspired by the unique glutamine metabolism pathway in cancer cells, herein, intelligent nanocatalytic theranostics is used to enhance intracellular reactive oxygen species (ROS) accumulation via the production of H2O2 by a biomimetic nanozyme, and simultaneously reduce ROS consumption via the depression of GSH synthesis by the glutamine metabolic inhibitor. In this reactor, nano-sized Au and Fe3O4 coloaded dendritic mesoporous silica nanoparticles (DMSN-Au-Fe3O4) serve as the bifunctional nanozyme, where intracellular glucose is catalyzed into H2O2 by the glucose oxidase-mimicking Au nanoparticles and then immediately transformed into ˙OH by the peroxidase-like Fe3O4 nanoparticles. Then, CB839, the glutaminase (GLS) inhibitor, is grafted on the nanozyme, blocking the glutamine pathway and GSH biosynthesis. As a result, the as-designed nanoplatform with a three-pronged integration of Au-mediated H2O2 self-supply, Fe3O4-triggered Fenton-like reaction, and glutamine pathway-mediated GSH depletion significantly boosts the CDT efficacy, achieving remarkable and specific antitumor properties both in vitro and in vivo. This work not only paves a new way for rationally designing multi-functional nanozymes for achieving high therapeutic efficacy, but also provides new insights into the construction of bioinspired synergetic therapy by combining CDT and a key anticancer pathway.

DOI: https://doi.org/10.1039/d2tb02194c
Front Genet. 2022 ;13 1030837

Establishing a glutamine metabolism-based model for predicting the prognosis of low-grade glioma.

Mingshi Zhang, Mingjun Li, Jinrui Liu, Zhicheng Gu, Yanmei Lu, Yu Long, Yuyi Hou.

  Background: The natural history of patients with low-grade glioma (LGG) varies widely, but most patients eventually deteriorate, leading to poor prognostic outcomes. We aim to develop biological models that can accurately predict the outcome of LGG prognosis. Methods: Prognostic genes for glutamine metabolism were searched by univariate Cox regression, and molecular typing was constructed. Functional enrichment analysis was done to evaluate potential prognostic-related pathways by analyzing differential genes in different subtypes. Enrichment scores of specific gene sets in different subtypes were measured by gene set enrichment analysis. Different immune infiltration levels among subtypes were calculated using algorithms such as CIBERSORT and ESTIMATE. Gene expression levels of prognostic-related gene signatures of glutamine metabolism phenotypes were used to construct a RiskScore model. Receiver operating characteristic curve, decision curve and calibration curve analyses were used to evaluate the reliability and validity of the risk model. The decision tree model was used to determine the best predictor variable ultimately. Results: We found that C1 had the worst prognosis and the highest level of immune infiltration, among which the highest macrophage infiltration can be found in the M2 stage. Moreover, most of the pathways associated with tumor development, such as MYC_TARGETS_V1 and EPITHELIAL_MESENCHYMAL_TRANSITION, were significantly enriched in C1. The wild-type IDH and MGMT hypermethylation were the most abundant in C1. A five-gene risk model related to glutamine metabolism phenotype was established with good performance in both training and validation datasets. The final decision tree demonstrated the RiskScore model as the most significant predictor of prognostic outcomes in individuals with LGG. Conclusion: The RiskScore model related to glutamine metabolism can be an exceedingly accurate predictor for LGG patients, providing valuable suggestions for personalized treatment.

Keywords:  decision tree; glutamine; low-grade glioma; molecular typing; prognostic model

DOI:  https://doi.org/10.3389/fgene.2022.1030837
PLoS One. 2022 ;17(12): e0278711

Ribitol alters multiple metabolic pathways of central carbon metabolism with enhanced glycolysis: A metabolomics and transcriptomics profiling of breast cancer.

Jason Driver Tucker, Ravi Doddapaneni, Pei Juan Lu, Qi Long Lu.

Breast cancer is heterogenous in development and cell population with prognoses being highly dependent on numerous factors from driving mutations, biomarker expression and variation in extracellular environment, all affecting response to therapies. Recently, much attention has been given to the role of metabolic alteration in cancers, expanding from the Warburg effect to highlight unique patterns in different cancer cell populations for improving diagnostic and therapeutic approaches. We recently reported on modulation of mannosylation of α-dystroglycan with the metabolite ribitol in breast cancer lines. Here we investigate the effects of pentose sugars ribitol, ribose, and xylitol media supplementation in breast cancer cells by metabolomics and differential gene expression profiling. This combined approach revealed distinctive patterns of alterations in metabolic pathways by ribitol, contrasted with the closely related pentose ribose and pentitol xylitol. Significantly, ribitol supplementation enhances utilization of glucose by glycolysis, whereas ribose improves oxidative phosphorylation and fatty acid synthesis. Ribitol supplementation also increased levels of reduced glutathione (associated with a decrease in oxidative phosphorylation, gluconeogenesis), where ribose supplementation elevated levels of oxidized glutathione (GSSG) indicating an increase in oxidative stress. Treatment with ribitol also enhanced nucleotide biosynthesis. The apparent TCA cycle dysregulation, with distinctive pattern in response to the individual pentitol and pentose, such as ribitol increasing succinate and fumarate while decreasing citrate, demonstrate the adaptive capability of cancer cells to nutritional environment. This metabolic reprogramming presents new avenues for developing targeted therapies to cancers with metabolites, especially in combination with other drug treatments.

DOI: https://doi.org/10.1371/journal.pone.0278711
Front Oncol. 2022 ;12 1029033

The impact of the microbiome in cancer: Targeting metabolism of cancer cells and host.

Jia-Ting Huang, Yu-Qin Mao.

  Abnormal metabolic alterations of cancer cells and the host play critical roles in the occurrence and development of tumors. Targeting cancer cells and host metabolism can provide novel diagnosis indicators and intervention targets for tumors. In recent years, it has been found that gut microbiota is involved in the metabolism of the host and cancer cells. Increasingly, gut microbiome and their metabolites have been demonstrated great influence on the tumor formation, prognosis and treatment. Specific gut microbial composition and metabolites are associated with the status of tumor in the host. Interventions on the gut microbiota can exert the protective effects on the tumor, through the manipulation of structure and its related metabolites. This may be the new approach to improve the efficacy of tumor prevention and treatment. Here, we discuss the effects and the underlying mechanisms of gut microbiota and microbial-derived metabolites in tumor progression and treatment.

Keywords:  host; metabolism; microbiome; therapy; tumor

DOI:  https://doi.org/10.3389/fonc.2022.1029033
Nitric Oxide. 2022 Dec 02. pii: S1089-8603(22)00125-2. [Epub ahead of print]

Nitric oxide regulation of cellular metabolism: Adaptive tuning of cellular energy.

Gregory Pappas, Melissa L Wilkinson, Andrew J Gow.

  Nitric oxide can interact with a wide range of proteins including many that are involved in metabolism. In this review we have summarized the effects of NO on glycolysis, fatty acid metabolism, the TCA cycle, and oxidative phosphorylation with reference to skeletal muscle. Low to moderate NO concentrations upregulate glucose and fatty acid oxidation, while higher NO concentrations shift cellular reliance toward a fully glycolytic phenotype. Moderate NO production directly inhibits pyruvate dehydrogenase activity, reducing glucose-derived carbon entry into the TCA cycle and subsequently increasing anaploretic reactions. NO directly inhibits aconitase activity, increasing reliance on glutamine for continued energy production. At higher or prolonged NO exposure, citrate accumulation can inhibit multiple ATP-producing pathways. Reduced TCA flux slows NADH/FADH entry into the ETC. NO can also inhibit the ETC directly, further limiting oxidative phosphorylation. Moderate NO production improves mitochondrial efficiency while improving O2 utilization increasing whole-body energy production. Long-term bioenergetic capacity may be increased because of NO-derived ROS, which participate in adaptive cellular redox signaling through AMPK, PCG1-α, HIF-1, and NF-κB. However, prolonged exposure or high concentrations of NO can result in membrane depolarization and opening of the MPT. In this way NO may serve as a biochemical rheostat matching energy supply with demand for optimal respiratory function.

Keywords:  Cellular respiration; Exercise; Glycolysis; Metabolism; Mitochondria; Nitric oxide

DOI:  https://doi.org/10.1016/j.niox.2022.11.006