bims-glucam 2024-06-02 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024–06–02
twenty papers selected by
Sreeparna Banerjee, Middle East Technical University

Oleic acid stimulates proliferation of RMG-1 ovarian cancer cells by activating the pentose phosphate pathway and glutamine metabolism.
Radiation-induced exosomes promote oral squamous cell carcinoma progression via enhancing SLC1A5-glutamine metabolism.
13C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 T cells.
IFRD1 promotes tumor cells "low-cost" survival under glutamine starvation via inhibiting histone H1.0 nucleophagy.
The glutamate/aspartate transporter EAAT1 is crucial for T-cell acute lymphoblastic leukemia proliferation and survival.
Comprehensive review of histone lactylation: Structure, function, and therapeutic targets.
Glutathione metabolism-related gene signature predicts prognosis and treatment response in low-grade glioma.
Adipocytes Are the Only Site of Glutamine Synthetase Expression Within the Lactating Mouse Mammary Gland.
Anticancer Effects of the Trivalent Organoarsenical 2-Amino-4-(dihydroxyarsinoyl) Butanoate.
Biomimetic copper-doped polypyrrole nanoparticles induce glutamine metabolism inhibition to enhance breast cancer cuproptosis and immunotherapy.
[Exploration of mechanism of total triterpenoids from fruits of Chaenomeles speciosa against senescent GES-1 cells induced by D-galactose based on Gln/GLS1/α-KG metabolic axis and mitochondrial apoptosis signaling pathway].
Research progress in the metabolic reprogramming of hepatocellular carcinoma (Review).
Breast cancer cell-secreted miR-199b-5p hijacks neurometabolic coupling to promote brain metastasis.
Exploring the mystery of tumor metabolism: Warburg effect and mitochondrial metabolism fighting side by side.
Cystine/glutamate antiporter xCT controls skeletal muscle glutathione redox, bioenergetics and differentiation.
Effects of glutamine and omega-3 fatty acids on intestinal neomucosa formation on colon serosa in rats.
Computational Insights into Protein Aging: Spontaneous Deamidation of Glutamine.
Glutathione-depleting Liposome Adjuvant for Augmenting the Efficacy of a Glutathione Covalent Inhibitor Oridonin for Acute Myeloid Leukemia Therapy.
The prowess of metabolomics in cancer research: current trends, challenges and future perspectives.
Insights into the regulation of malate dehydrogenase: inhibitors, activators, and allosteric modulation by small molecules.

Biochem Biophys Res Commun. 2024 May 24. pii: S0006-291X(24)00698-3. [Epub ahead of print]722 150162

Oleic acid stimulates proliferation of RMG-1 ovarian cancer cells by activating the pentose phosphate pathway and glutamine metabolism.

Takeru Tamaki, Nobuyuki Fukushima.

  Extracellular fatty acids (FAs) play an important role in regulating cellular functions such as cell proliferation, survival, and migration. The effects of oleic acid (OA) on cancer cells vary depending on the cell type. Our prior study showed that two distinct ovarian cancer cell lines, RMG-1 and HNOA, proliferate in response to OA, but they differ with respect to glucose utilization. Here, we aimed to elucidate the mechanism(s) by which OA stimulates proliferation of RMG-1 cells. We found that OA stimulates RMG-1 proliferation by activating the FA transporter CD36. OA also increases uptake of glucose and glutamine, which subsequently activate the pentose phosphate pathway (PPP) and glutamine metabolism, respectively. Given that ribose 5-phosphate derived from the PPP is utilized for glutamine metabolism and the subsequent de novo nucleotide synthesis, our findings suggest that OA affects the PPP associated with Gln metabolism, rather than glycolysis associated with glutaminolysis; this leads ultimately to activation of DNA synthesis, which is required for cell proliferation. This selective activation by OA contrasts with the mechanisms observed in HNOA cells, in which OA-induced cell proliferation is driven by transcriptional regulation of the GLUT gene. The diverse responses of cancer cells to OA may be attributed to distinct mechanisms of OA reception and/or different metabolic pathways activated by OA.

Keywords:  CD36; Glutamine metabolism; Oleic acid; Ovarian cancer cell; Pentose phosphate pathway; de novo nucleotide synthesis

DOI:  https://doi.org/10.1016/j.bbrc.2024.150162
J Oral Pathol Med. 2024 May 27.

Radiation-induced exosomes promote oral squamous cell carcinoma progression via enhancing SLC1A5-glutamine metabolism.

Rongchun Yang, Siyuan Zhang, Lixuan Wang, Yingyao Chen, Xiaobing Chen, Juan Xia, Xianyue Ren, Bin Cheng, Xijuan Chen.

   BACKGROUND: Radiotherapy (RT) can drive cancer cells to enter a state of cellular senescence in which cells can secrete senescence-associated secretory phenotype (SASP) and produce small extracellular vesicles (sEVs) to interact with cells in the tumor microenvironment (TME). Tumor-derived sEVs that are taken up by recipient cells contribute to cancer cell metabolic plasticity, resistance to anticancer therapy, and adaptation to the TME. However, how radiation-induced sEVs support oral squamous cell carcinoma (OSCC) progression remains unclear.
METHODS: Beta-galactosidase staining and SASP mRNA expression analysis were used to evaluate the senescence-associated activity of OSCC cells after irradiation. Nanoparticle tracking analysis was performed to identify radiation-induced sEVs. Liquid chromatography-tandem mass spectrometry (LC-MS) was used to explore changes in the levels of proteins in radiation-induced sEVs. Cell Counting Kit-8 and colony formation assays were performed to investigate the function of radiation-induced SASP and sEVs in vitro. A xenograft tumor model was established to investigate the functions of radiation-induced sEVs and V-9302 in vivo as well as the underlying mechanisms. Bioinformatics analysis was performed to determine the relationship between glutamine metabolism and OSCC recurrence.
RESULTS: We determined that the radiation-induced SASP triggered OSCC cell proliferation. Additionally, radiation-induced sEVs exacerbated OSCC cell malignancy. LC-MS/MS and bioinformatics analyses revealed that SLC1A5, which is a cellular receptor that participates in glutamine uptake, was significantly enriched in radiation-induced sEVs. In vitro and in vivo, inhibiting SLC1A5 could block the oncogenic effects of radiation-induced sEVs in OSCC.
CONCLUSION: Radiation-induced sEVs might promote the proliferation of unirradiated cancer cells by enhancing glutamine metabolism; this might be a novel molecular mechanism underlying radiation resistance in OSCC patients.

Keywords:  OSCC; exosome; glutamine metabolism; radiotherapy

DOI:  https://doi.org/10.1111/jop.13561
Sci Adv. 2024 May 31. 10(22): eadj1431

13C metabolite tracing reveals glutamine and acetate as critical in vivo fuels for CD8 T cells.

Eric H Ma, Michael S Dahabieh, Lisa M DeCamp, Irem Kaymak, Susan M Kitchen-Goosen, Brandon M Oswald, Joseph Longo, Dominic G Roy, Mark J Verway, Radia M Johnson, Bozena Samborska, Lauren R Duimstra, Catherine A Scullion, Mya Steadman, Matthew Vos, Thomas P Roddy, Connie M Krawczyk, Kelsey S Williams, Ryan D Sheldon, Russell G Jones.

Infusion of 13C-labeled metabolites provides a gold standard for understanding the metabolic processes used by T cells during immune responses in vivo. Through infusion of 13C-labeled metabolites (glucose, glutamine, and acetate) in Listeria monocytogenes-infected mice, we demonstrate that CD8 T effector (Teff) cells use metabolites for specific pathways during specific phases of activation. Highly proliferative early Teff cells in vivo shunt glucose primarily toward nucleotide synthesis and leverage glutamine anaplerosis in the tricarboxylic acid (TCA) cycle to support adenosine triphosphate and de novo pyrimidine synthesis. In addition, early Teff cells rely on glutamic-oxaloacetic transaminase 1 (Got1)-which regulates de novo aspartate synthesis-for effector cell expansion in vivo. CD8 Teff cells change fuel preference over the course of infection, switching from glutamine- to acetate-dependent TCA cycle metabolism late in infection. This study provides insights into the dynamics of Teff metabolism, illuminating distinct pathways of fuel consumption associated with CD8 Teff cell function in vivo.

DOI: https://doi.org/10.1126/sciadv.adj1431
Cell Discov. 2024 May 28. 10(1): 57

IFRD1 promotes tumor cells "low-cost" survival under glutamine starvation via inhibiting histone H1.0 nucleophagy.

Yabin Huang, Fanzheng Meng, Taofei Zeng, Rick Francis Thorne, Lifang He, Qingrui Zha, Hairui Li, Hong Liu, Chuandong Lang, Wanxiang Xiong, Shixiang Pan, Dalong Yin, Mian Wu, Xuedan Sun, Lianxin Liu.

Glutamine addiction represents a metabolic vulnerability of cancer cells; however, effective therapeutic targeting of the pathways involved remains to be realized. Here, we disclose the critical role of interferon-related developmental regulator 1 (IFRD1) in the adaptive survival of hepatocellular carcinoma (HCC) cells during glutamine starvation. IFRD1 is induced under glutamine starvation to inhibit autophagy by promoting the proteasomal degradation of the key autophagy regulator ATG14 in a TRIM21-dependent manner. Conversely, targeting IFRD1 in the glutamine-deprived state increases autophagy flux, triggering cancer cell exhaustive death. This effect largely results from the nucleophilic degradation of histone H1.0 and the ensuing unchecked increases in ribosome and protein biosynthesis associated with globally enhanced chromatin accessibility. Intriguingly, IFRD1 depletion in preclinical HCC models synergizes with the treatment of the glutaminase-1 selective inhibitor CB-839 to potentiate the effect of limiting glutamine. Together, our findings reveal how IFRD1 supports the adaptive survival of cancer cells under glutamine starvation, further highlighting the potential of IFRD1 as a therapeutic target in anti-cancer applications.

DOI: https://doi.org/10.1038/s41421-024-00668-x
Haematologica. 2024 May 30.

The glutamate/aspartate transporter EAAT1 is crucial for T-cell acute lymphoblastic leukemia proliferation and survival.

Vesna S Stanulović, Shorog Al Omair, Michelle A C Reed, Jennie Roberts, Sandeep Potluri, Taylor Fulton-Ward, Nancy Gudgeon, Emma L Bishop, Juliette Roels, Tracey A Perry, Sovan Sarkar, Guy Pratt, Tom Taghon, Sarah Dimeloe, Ulrich L Günther, Christian Ludwig, Maarten Hoogenkamp.

T-cell acute lymphoblastic leukemia (T-ALL) is a cancer of the immune system. Approximately 20% of paediatric and 50% of adult T-ALL patients have refractory disease or relapse and die from the disease. To improve patient outcome new therapeutics are needed. With the aim to identify new therapeutic targets, we combined the analysis of T-ALL gene expression and metabolism to identify the metabolic adaptations that T-ALL cells exhibit. We found that glutamine uptake is essential for T-ALL proliferation. Isotope tracing experiments showed that glutamine fuels aspartate synthesis through the TCA cycle and that glutamine and glutamine-derived aspartate together supply three nitrogen atoms in purines and all but one atom in pyrimidine rings. We show that the glutamate-aspartate transporter EAAT1 (SLC1A3), which is normally expressed in the central nervous system, is crucial for glutamine conversion to aspartate and nucleotides and that T-ALL cell proliferation depends on EAAT1 function. Through this work, we identify EAAT1 as a novel therapeutic target for T-ALL treatment.

DOI: https://doi.org/10.3324/haematol.2023.283471
Biochem Pharmacol. 2024 May 29. pii: S0006-2952(24)00314-9. [Epub ahead of print] 116331

Comprehensive review of histone lactylation: Structure, function, and therapeutic targets.

Kaiwen Xu, Keyi Zhang, Yanshuang Wang, Yue Gu.

  Histone lysine lactylation (Kla) has emerged as a distinct epigenetic modification that differs markedly from established acylation modifications through the unique addition of a lactyl group to a lysine residue. Such modifications not only alter nucleosome structure but also significantly impact chromatin dynamics and gene expression, thus playing a crucial role in cellular metabolism, inflammatory responses, and embryonic development. The association of histone Kla with various metabolic processes, particularly glycolysis and glutamine metabolism, underscores its pivotal role in metabolic reprogramming, including in cancerous tissues, where it contributes to tumorigenesis, immune evasion, and angiogenesis. In addition, histone Kla is involved in the pathogenesis of various diseases, particularly several cancers and neurodegenerative diseases. The identification of histone Kla opens new avenues for therapeutic interventions targeting specific Kla sites. In this review, we summarize the differences between histone Kla modifications and other acylation modifications, discuss the mechanisms and roles of histone Kla in disease, and conclude by describing existing drugs and potential targets. This study provides new insights into the mechanisms linking histone Kla to diseases and into the discovery of new drugs and targets.

Keywords:  Acylation modifications; Drug targets; Epigenetic regulation; Histone lactylation; Metabolic pathways

DOI:  https://doi.org/10.1016/j.bcp.2024.116331
Aging (Albany NY). 2024 May 30. 16

Glutathione metabolism-related gene signature predicts prognosis and treatment response in low-grade glioma.

Zaidong Deng, Jing Luo, Jing Ma, Youngnam N Jin, Yanxun V Yu.

  Cancer cells can induce molecular changes that reshape cellular metabolism, creating specific vulnerabilities for targeted therapeutic interventions. Given the importance of reactive oxygen species (ROS) in tumor development and drug resistance, and the abundance of reduced glutathione (GSH) as the primary cellular antioxidant, we examined an integrated panel of 56 glutathione metabolism-related genes (GMRGs) across diverse cancer types. This analysis revealed a remarkable association between GMRGs and low-grade glioma (LGG) survival. Unsupervised clustering and a GMRGs-based risk score (GS) categorized LGG patients into two groups, linking elevated glutathione metabolism to poorer prognosis and treatment outcomes. Our GS model outperformed established clinical prognostic factors, acting as an independent prognostic factor. GS also exhibited correlations with pro-tumor M2 macrophage infiltration, upregulated immunosuppressive genes, and diminished responses to various cancer therapies. Experimental validation in glioma cell lines confirmed the critical role of glutathione metabolism in glioma cell proliferation and chemoresistance. Our findings highlight the presence of a unique metabolic susceptibility in LGG and introduce a novel GS system as a highly effective tool for predicting the prognosis of LGG.

Keywords:  cancer treatment; glutathione metabolism; low-grade glioma (LGG); prognosis; risk signature

DOI:  https://doi.org/10.18632/aging.205881
Curr Dev Nutr. 2024 Jun;8(6): 102168

Adipocytes Are the Only Site of Glutamine Synthetase Expression Within the Lactating Mouse Mammary Gland.

Huyen Le, Mai Nguyen, Helena Emilia Ccc Manso, Michelle D Wang, Malcolm Watford.

   Background: Glutamine in milk is believed to play an important role in neonatal intestinal maturation and immune function. For lactating mothers, glutamine utilization is increased to meet the demands of the enlarged intestine and milk production. However, the source of such glutamine during lactation has not been studied.
Objectives: We aimed to assess the effects of lactation on the expression of glutamine synthetase (GS) in the mammary gland and other tissues of lactating mice.
Methods: Mouse tissues were sampled at 4 time points: 8-wk-old (virgin, control), post-delivery day 5 (PD5, early lactation), PD15 (peak lactation), and involution (4 days after weaning at PD21). We examined the gene expression and protein concentrations of GS and the first 2 enzymes of branched-chain amino acid catabolism: branched-chain aminotransferase 2 (BCAT2) and branched-chain ketoacid dehydrogenase subunit E1α (BCKDHA).
Results: The messenger RNA (mRNA) expression and protein concentrations of GS in mammary glands were significantly lower at PD5 and PD15 compared with the control but were restored at involution. Within the mammary gland, GS protein was only detected in adipocytes with no evidence of presence in mammary epithelial cells. Compared with the control, mRNA and protein concentrations of BCAT2 and BCKDHA in mammary glands significantly decreased during lactation and involution. No changes in GS protein concentrations during lactation were found in the liver, skeletal muscle, and lung. In non-mammary adipose tissue, GS protein abundance was higher during lactation compared with the virgin.
Conclusions: This work shows that, within the mouse mammary gland, GS is only expressed in adipocytes and that the relative GS abundance in mammary gland sections is lower during lactation. This suggests that mammary adipocytes may be a site of glutamine synthesis in the lactating mouse. Identifying the sources of glutamine production during lactation is important for optimizing milk glutamine concentration to enhance neonatal and maternal health.

Keywords:  BCAA; adipocytes; glutamine; glutamine synthetase; lactation; mammary gland; mouse

DOI:  https://doi.org/10.1016/j.cdnut.2024.102168
Organometallics. 2024 May 27. 43(10): 1137-1142

Anticancer Effects of the Trivalent Organoarsenical 2-Amino-4-(dihydroxyarsinoyl) Butanoate.

Venkadesh Sarkarai Nadar, Kunie Yoshinaga-Sakurai, Barry P Rosen.

According to the National Cancer Institute, breast cancer is a leading cause of death in women. The lack of progesterone and estrogen receptors in triple-negative breast cancer (TNBC) cells results in a lack of response to hormonal, monoclonal, or tyrosine kinase inhibitor therapies. Despite intensive drug discovery, there is still no approved targeted treatment for TNBC. The metalloid arsenic has been used in herbal medicines, antibiotics, and chemotherapeutic drugs for centuries. This paper demonstrates that a trivalent arsenic-containing, nonproteogenic amino acid, R-AST-OH (2-amino-4-(dihydroxyarsinoyl) butanoate), inhibits kidney-type glutaminase (KGA), the enzyme that controls glutamine metabolism and is correlated with tumor malignancy. Cell-based assays using the TNBC MDA-MB-231 and HCC1569 cell lines showed that R-AST-OH kills TNBC cells and is not cytotoxic to a control cell line. The results of in silico molecular docking predictions indicate that R-AST-OH binds to the glutamine binding site and forms a covalent bond with an active site cysteine residue. We hypothesize that R-AST-OH is a single warhead for KGA that irreversibly binds to KGA through the formation of an As-S bond. We propose that R-AST-OH is a promising lead compound for the design of new drugs for the treatment of TNBC.

DOI: https://doi.org/10.1021/acs.organomet.4c00082
J Control Release. 2024 May 27. pii: S0168-3659(24)00329-8. [Epub ahead of print]

Biomimetic copper-doped polypyrrole nanoparticles induce glutamine metabolism inhibition to enhance breast cancer cuproptosis and immunotherapy.

Ni Zhang, Wei Ping, Kexiang Rao, Zhenlin Zhang, Rong Huang, Daoming Zhu, Guoxin Li, Shipeng Ning.

  Cuproptosis, a newly discovered mechanism of inducing tumor cell death, primarily relies on the intracellular accumulation of copper ions. The utilization of Cu-based nanomaterials to induce cuproptosis holds promising prospects in future biomedical applications. However, the presence of high levels of glutathione (GSH) within tumor cells hinders the efficacy of cuproptosis. In this study, we have developed a BPTES-loaded biomimetic Cu-doped polypyrrole nanoparticles (CuP) nanosystem (PCB) for enhanced cuproptosis and immune modulation. PCB comprises an internal BPTES and CuP core and an external platelet membrane (PM) that facilitates active targeting to tumor sites following intravenous administration. Subsequently, PCB effectively suppresses glutaminase (GLS1) activity, thereby reducing GSH content. Moreover, CuP catalyze intracellular H2O2, amplifying oxidative stress while simultaneously inducing dihydrolipoyl transacetylase (DLAT) oligomerization through released Cu2+, resulting in cuproptosis. PCB not only inhibits primary tumors but also exhibits inhibitory effects on abscopal tumors. This work represents the first instance where GLS inhibition has been employed to enhance cuproptosis and immunotherapy. It also provides valuable insights into further investigations on cuproptosis.

Keywords:  Cu-doped polypyrrole nanoparticles; Cuproptosis; Glutathione; Platelet membrane; Tumor immunotherapy

DOI:  https://doi.org/10.1016/j.jconrel.2024.05.045
Zhongguo Zhong Yao Za Zhi. 2024 Apr;49(8): 2230-2246

[Exploration of mechanism of total triterpenoids from fruits of Chaenomeles speciosa against senescent GES-1 cells induced by D-galactose based on Gln/GLS1/α-KG metabolic axis and mitochondrial apoptosis signaling pathway].

Jun-Yu He, Jia-Xin Yang, Shi-Ying Qin, Jing-Qi Zheng, Yi-Ran Guo, Tian-Xing Ma.

  Total triterpenoids from the fruits of Chaenomeles speciosa(TCS) are active components in the prevention and treatment of gastric mucosal damage, which have potential anti-aging effects. However, it is still unclear whether TCS can improve gastric aging, especially its molecular mechanism against gastric aging. On this basis, this study explored the effect and mechanism of TCS on senescent GES-1 cells induced by D-galactose(D-gal) to provide scientific data for the clinical use of TCS to prevent gastric aging. GES-1 cells cultured in vitro and those transfected with overexpression GLS1(GLS1-OE) plasmid of glutaminase 1(GLS1) were induced to aging by D-gal, and then TCS and or GLS1 inhibitor bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide(BPTES) were given. Cell survival rate, positive rate of β-galactosidase(SA-β-gal) staining, mitochondrial membrane potential(MMP), and apoptosis were investigated. GLS1 activity, levels of glutamine(Gln), glutamate(Glu), α-ketoglutarate(α-KG), urea, and ammonia in supernatant and cells were detected by enzyme-linked immunosorbent assay(ELISA) and colorimetric methods. The mRNA and protein expressions of GLS1 and the related genes of the mitochondrial apoptosis signaling pathway were measured by real-time fluorescence quantitative PCR and Western blot. The results manifested that compared with the D-gal model group and GLS1-OE D-gal model group, TCS significantly decreased the SA-β-gal staining positive cell rate and MMP of D-gal-induced senescent GES-1 cells and GLS1-OE senescent GES-1 cells, inhibited the survival of senescent cells, and promoted their apoptosis(P<0.01). It decreased the activity of GLS1 and the content of Gln, Glu, α-KG, urea, and ammonia in supernatant and cell(P<0.01), reduced the concentration of cytochrome C(Cyto C) in mitochondria and the mRNA and protein expressions of GLS1 and proliferating nuclear antigen in cells(P<0.01). The mRNA expression of Bcl-2 and Bcl-xl, the protein expression of pro-caspase-9 and pro-caspase-3, and the ratio of Bcl-2/Bax and Bcl-xl/Bad in cells were decreased(P<0.01). Cyto C concentration in the cytoplasm, the mRNA expressions of Bax, Bad, apoptosis protease activating factor 1(Apaf-1), and protein expressions of cleaved-caspase-9, cleaved-caspase-3, cleaved-PARP-1 were increased(P<0.01). The aforementioned results indicate that TCS can counteract the senescent GES-1 cells induced by D-gal, and its mechanism may be closely related to suppressing the Gln/GLS1/α-KG metabolic axis, activating the mitochondrial apoptosis pathway, and thereby accelerating the apoptosis of the senescent cells and eliminating senescent cells.

Keywords:  D-galactose; GES-1 cells; glutamine/glutaminase 1/α-ketoglutarate metabolic axis; mitochondrial apoptosis signaling pathway; senescence; total triterpenoids from the fruits of Chaenomeles speciosa

DOI:  https://doi.org/10.19540/j.cnki.cjcmm.20231212.707
Mol Med Rep. 2024 Jul;pii: 131. [Epub ahead of print]30(1):

Research progress in the metabolic reprogramming of hepatocellular carcinoma (Review).

Wenyue Gao, Jing Wang, Yuting Xu, Hongbo Yu, Sitong Yi, Changchuan Bai, Qingwei Cong, Ying Zhu.

  Hepatocellular carcinoma (HCC) is the most common primary liver malignancy and its morbidity is increasing worldwide due to increasing prevalence. Metabolic reprogramming has been recognized as a hallmark of cancer and serves a role in cancer progression. Glucose, lipids and amino acids are three major components whose altered metabolism can directly affect the energy production of cells, including liver cancer cells. Nutrients and energy are indispensable for the growth and proliferation of cancer cells, thus altering the metabolism of hepatoma cells can inhibit the progression of HCC. The present review summarizes recent studies on tumour regulatory molecules, including numerous noncoding RNAs, oncogenes and tumour suppressors, which regulate the metabolic activities of glucose, lipids and amino acids by targeting key enzymes, signalling pathways or interactions between the two. These regulatory molecules can regulate the rapid proliferation of cancer cells, tumour progression and treatment resistance. It is thought that these tumour regulatory factors may serve as therapeutic targets or valuable biomarkers for HCC, with the potential to mitigate HCC drug resistance. Furthermore, the advantages and disadvantages of metabolic inhibitors as a treatment approach for HCC, as well as possible solutions are discussed, providing insights for developing more effective treatment strategies for HCC.

Keywords:  hepatocellular carcinoma; metabolic reprogramming; noncoding RNAs; oncogenes; tumour suppressors

DOI:  https://doi.org/10.3892/mmr.2024.13255
Nat Commun. 2024 May 29. 15(1): 4549

Breast cancer cell-secreted miR-199b-5p hijacks neurometabolic coupling to promote brain metastasis.

Xianhui Ruan, Wei Yan, Minghui Cao, Ray Anthony M Daza, Miranda Y Fong, Kaifu Yang, Jun Wu, Xuxiang Liu, Melanie Palomares, Xiwei Wu, Arthur Li, Yuan Chen, Rahul Jandial, Nicholas C Spitzer, Robert F Hevner, Shizhen Emily Wang.

Breast cancer metastasis to the brain is a clinical challenge rising in prevalence. However, the underlying mechanisms, especially how cancer cells adapt a distant brain niche to facilitate colonization, remain poorly understood. A unique metabolic feature of the brain is the coupling between neurons and astrocytes through glutamate, glutamine, and lactate. Here we show that extracellular vesicles from breast cancer cells with a high potential to develop brain metastases carry high levels of miR-199b-5p, which shows higher levels in the blood of breast cancer patients with brain metastases comparing to those with metastatic cancer in other organs. miR-199b-5p targets solute carrier transporters (SLC1A2/EAAT2 in astrocytes and SLC38A2/SNAT2 and SLC16A7/MCT2 in neurons) to hijack the neuron-astrocyte metabolic coupling, leading to extracellular retention of these metabolites and promoting cancer cell growth. Our findings reveal a mechanism through which cancer cells of a non-brain origin reprogram neural metabolism to fuel brain metastases.

DOI: https://doi.org/10.1038/s41467-024-48740-0
Cell Signal. 2024 May 28. pii: S0898-6568(24)00207-9. [Epub ahead of print] 111239

Exploring the mystery of tumor metabolism: Warburg effect and mitochondrial metabolism fighting side by side.

Yongxin Yu, Yulang Jiang, Christian Glandorff, Mingyu Sun.

  The metabolic reconfiguration of tumor cells constitutes a pivotal aspect of tumor proliferation and advancement. This study delves into two primary facets of tumor metabolism: the Warburg effect and mitochondrial metabolism, elucidating their contributions to tumor dominance. The Warburg effect facilitates efficient energy acquisition by tumor cells through aerobic glycolysis and lactic acid fermentation, offering metabolic advantages conducive to growth and proliferation. Simultaneously, mitochondrial metabolism, serving as the linchpin of sustained tumor vitality, orchestrates the tricarboxylic acid cycle and electron transport chain, furnishing a steadfast and dependable wellspring of biosynthesis for tumor cells. Regarding targeted therapy, this discourse examines extant strategies targeting tumor glycolysis and mitochondrial metabolism, underscoring their potential efficacy in modulating tumor metabolism while envisaging future research trajectories and treatment paradigms in the realm of tumor metabolism. By means of a thorough exploration of tumor metabolism, this study aspires to furnish crucial insights into the regulation of tumor metabolic processes, thereby furnishing valuable guidance for the development of novel therapeutic modalities. This comprehensive deliberation is poised to catalyze advancements in tumor metabolism research and offer novel perspectives and pathways for the formulation of cancer treatment strategies in the times ahead.

Keywords:  Metabolic reprogramming; Mitochondria; Targeted therapy; Tumor; Warburg effect

DOI:  https://doi.org/10.1016/j.cellsig.2024.111239
Redox Biol. 2024 May 25. pii: S2213-2317(24)00191-5. [Epub ahead of print]73 103213

Cystine/glutamate antiporter xCT controls skeletal muscle glutathione redox, bioenergetics and differentiation.

Michel N Kanaan, Chantal A Pileggi, Charbel Y Karam, Luke S Kennedy, Claire Fong-McMaster, Miroslava Cuperlovic-Culf, Mary-Ellen Harper.

  Cysteine, the rate-controlling amino acid in cellular glutathione synthesis is imported as cystine, by the cystine/glutamate antiporter, xCT, and subsequently reduced to cysteine. As glutathione redox is important in muscle regeneration in aging, we hypothesized that xCT exerts upstream control over skeletal muscle glutathione redox, metabolism and regeneration. Bioinformatic analyses of publicly available datasets revealed that expression levels of xCT and GSH-related genes are inversely correlated with myogenic differentiation genes. Muscle satellite cells (MuSCs) isolated from Slc7a11sut/sut mice, which harbour a mutation in the Slc7a11 gene encoding xCT, required media supplementation with 2-mercaptoethanol to support cell proliferation but not myotube differentiation, despite persistently lower GSH. Slc7a11sut/sut primary myotubes were larger compared to WT myotubes, and also exhibited higher glucose uptake and cellular oxidative capacities. Immunostaining of myogenic markers (Pax7, MyoD, and myogenin) in cardiotoxin-damaged tibialis anterior muscle fibres revealed greater MuSC activation and commitment to differentiation in Slc7a11sut/sut muscle compared to WT mice, culminating in larger myofiber cross-sectional areas at 21 days post-injury. Slc7a11sut/sut mice subjected to a 5-week exercise training protocol demonstrated enhanced insulin tolerance compared to WT mice, but blunted muscle mitochondrial biogenesis and respiration in response to exercise training. Our results demonstrate that the absence of xCT inhibits cell proliferation but promotes myotube differentiation by regulating cellular metabolism and glutathione redox. Altogether, these results support the notion that myogenesis is a redox-regulated process and may help inform novel therapeutic approaches for muscle wasting and dysfunction in aging and disease.

Keywords:  Glutathione; Glycolysis; Mitochondria; Myogenesis; Oxidative phosphorylation; Redox

DOI:  https://doi.org/10.1016/j.redox.2024.103213
Turk J Med Sci. 2024 ;54(1): 59-68

Effects of glutamine and omega-3 fatty acids on intestinal neomucosa formation on colon serosa in rats.

Mehmet Köstek, Uygar Demir, Ramazan Uçak, Burak Yasin Avci, Aydın Ünal, Osman Bilgin Gülçiçek, Ozan Çalişkan, Bülent Çitgez, Erdinç Serin, Sıtkı Gürkan Yetkin, Mehmet Mihmanli, Mehmet Uludağ.

   Background/aim: Intestinal neomucosa formation is a technique defined for the treatment of short bowel syndrome. This study evaluates the effect of glutamine and omega-3 fatty acids on the growth of intestinal neomucosa on the colonic serosal surface has been evaluated.
Materials and methods: Thirty-two adult male Sprague-Dawley rats were randomly divided into 4 groups: sham, control, glutamine, and omega-3. Laparotomy was performed on all groups. For rats other than the sham group, a 1-cm full-thickness incision was made 4 cm proximal to the ileocecal valve, and colonic serosal surface was sutured as a serosal patch over these openings. By using the oral gavage technique, the glutamine group was ingested with 200 mg/kg/day of glutamine, and the omega-3 group was ingested with 100 mg/kg/day of omega-3 fatty acids. At the end of 14 days, the rats were euthanized, blood specimens were collected, and intestinal segments, including serosal patches, were excised.
Results: Transforming growth factor-beta was significantly lower in the glutamine group compared to the control group. Similarly, fibroblast growth factor-2 was significantly lower in the glutamine group compared to the sham group. Intestinal neomucosa formation was observed in 100% of rats in the glutamine group. In the control and omega-3 groups, intestinal neomucosa formation was observed in 57.1% and 60% of rats, respectively. The inflammatory response, granulation tissue formation, and fibroblastic activity were more severe in the rats of the glutamine and omega-3 groups.
Conclusion: The intestinal neomucosa formation is an experimental technique, and both glutamine and omega-3 fatty acids have the potential to positively affect inflammatory response, granulation tissue formation, and fibroblastic activity. Specifically, glutamine has a favorable effect on intestinal neomucosa formation.

Keywords:  Glutamine; intestinal neomucosa; omega-3 fatty acids; short bowel syndrome

DOI:  https://doi.org/10.55730/1300-0144.5766
J Phys Chem B. 2024 May 30.

Computational Insights into Protein Aging: Spontaneous Deamidation of Glutamine.

Dananjana V Wijerathne, Sedat Karabulut, James W Gauld.

Spontaneous deamidation of amino acids is a physiologically important process, particularly for protein aging and diseases. Despite its widespread occurrence, the mechanism of glutamine deamidation particularly within proteins remains poorly understood. We have used a multiscale computational approach to investigate glutamine deamidation in the tripeptide Glycine-Glutamine-Glycine (Gly-Gln-Gly) and γS-Crystallin protein. Specifically, both the 5- and 6-membered water-assisted deamidation pathways in the tripeptide have been elucidated and compared. Both are found to occur in three stages: iminol formation, cyclization, and deamination. The rate-limiting step in each mechanism is nucleophilic attack of the backbone iminol nitrogen, formed in the first stage, at the glutamine's side-chain carbonyl carbon. For the 6- and 5-membered mechanisms, this occurs with a free energy cost of 136.4 and 179.5 kJ mol-1, respectively. Thus, overall, in the Gly-Gln-Gly tripeptide, the 6-membered pathway is preferred. Furthermore, the free energies for forming cyclic intermediates and products at selected Gln residues (based on experimentally reported % deamidation) in γS-Crystallin have been obtained. It is found that the 5-membered product complex is exergonic at -25.3 kJ mol-1, while the 6-membered product complex is calculated to be endergonic at 90.7 kJ mol-1. Thus, the deamidation pathway in folded and constrained proteins may not exclusively follow the 6-membered route. Molecular dynamics (MD) simulations of γS-Crystallin indicate that deamidation is more likely to occur when two or more water molecules are in the proximity of the glutamine residue. Consequently, significant conformational changes are found to accompany Gln120 deamidation in γS-Crystallin. This in turn can influence water availability at the other Gln residues considered and hence potentially their deamidation. Collectively, these results provide comprehensive insights into spontaneous water-assisted deamidation of glutamine residues in peptides and into the role and impact of Gln deamidation in proteins.

DOI: https://doi.org/10.1021/acs.jpcb.3c07628
J Nanobiotechnology. 2024 May 30. 22(1): 299

Glutathione-depleting Liposome Adjuvant for Augmenting the Efficacy of a Glutathione Covalent Inhibitor Oridonin for Acute Myeloid Leukemia Therapy.

Yi Liu, Xiaoning Wang, Hui Feng, Xinyan Li, Runyu Yang, Mengyao Zhang, Yue Du, Ruimin Liu, Minna Luo, Zhiyi Li, Bo Liu, Jincheng Wang, Wenjuan Wang, Feifei An, Fan Niu, Pengcheng He.

   BACKGROUND: Discrepancies in the utilization of reactive oxygen species (ROS) between cancer cells and their normal counterparts constitute a pivotal juncture for the precise treatment of cancer, delineating a noteworthy trajectory in the field of targeted therapies. This phenomenon is particularly conspicuous in the domain of nano-drug precision treatment. Despite substantial strides in employing nanoparticles to disrupt ROS for cancer therapy, current strategies continue to grapple with challenges pertaining to efficacy and specificity. One of the primary hurdles lies in the elevated levels of intracellular glutathione (GSH). Presently, predominant methods to mitigate intracellular GSH involve inhibiting its synthesis or promoting GSH efflux. However, a conspicuous gap remains in the absence of a strategy capable of directly and efficiently clearing GSH.
METHODS: We initially elucidated the chemical mechanism underpinning oridonin, a diminutive pharmacological agent demonstrated to perturb reactive oxygen species, through its covalent interaction with glutathione. Subsequently, we employed the incorporation of maleimide-liposomes, renowned for their capacity to disrupt the ROS delivery system, to ameliorate the drug's water solubility and pharmacokinetics, thereby enhancing its ROS-disruptive efficacy. In a pursuit to further refine the targeting for acute myeloid leukemia (AML), we harnessed the maleic imide and thiol reaction mechanism, facilitating the coupling of Toll-like receptor 2 (TLR2) peptides to the liposomes' surface via maleic imide. This strategic approach offers a novel method for the precise removal of GSH, and its enhancement endeavors are directed towards fortifying the precision and efficacy of the drug's impact on AML targets.
RESULTS: We demonstrated that this peptide-liposome-small molecule machinery targets AML and consequently induces cell apoptosis both in vitro and in vivo through three disparate mechanisms: (I) Oridonin, as a Michael acceptor molecule, inhibits GSH function through covalent bonding, triggering an initial imbalance of oxidative stress. (II) Maleimide further induces GSH exhaustion, aggravating redox imbalance as a complementary augment with oridonin. (III) Peptide targets TLR2, enhances the directivity and enrichment of oridonin within AML cells.
CONCLUSION: The rationally designed nanocomplex provides a ROS drug enhancement and targeted delivery platform, representing a potential solution by disrupting redox balance for AML therapy.

Keywords:  AML therapeutics; Glutathione inhibitor; Oridonin; Peptide-based drug delivery; ROS

DOI:  https://doi.org/10.1186/s12951-024-02574-6
Mol Cell Biochem. 2024 May 30.

The prowess of metabolomics in cancer research: current trends, challenges and future perspectives.

Khushman Taunk, Saikiran Jajula, Praneeta Pradip Bhavsar, Mahima Choudhari, Sadanand Bhanuse, Anup Tamhankar, Tufan Naiya, Bhargab Kalita, Srikanth Rapole.

  Cancer due to its heterogeneous nature and large prevalence has tremendous socioeconomic impacts on populations across the world. Therefore, it is crucial to discover effective panels of biomarkers for diagnosing cancer at an early stage. Cancer leads to alterations in cell growth and differentiation at the molecular level, some of which are very unique. Therefore, comprehending these alterations can aid in a better understanding of the disease pathology and identification of the biomolecules that can serve as effective biomarkers for cancer diagnosis. Metabolites, among other biomolecules of interest, play a key role in the pathophysiology of cancer whose levels are significantly altered while 'reprogramming the energy metabolism', a cellular condition favored in cancer cells which is one of the hallmarks of cancer. Metabolomics, an emerging omics technology has tremendous potential to contribute towards the goal of investigating cancer metabolites or the metabolic alterations during the development of cancer. Diverse metabolites can be screened in a variety of biofluids, and tumor tissues sampled from cancer patients against healthy controls to capture the altered metabolism. In this review, we provide an overview of different metabolomics approaches employed in cancer research and the potential of metabolites as biomarkers for cancer diagnosis. In addition, we discuss the challenges associated with metabolomics-driven cancer research and gaze upon the prospects of this emerging field.

Keywords:  Cancer biomarkers; Mass spectrometry; Metabolites; Metastasis; Targeted metabolomics; Untargeted metabolomics

DOI:  https://doi.org/10.1007/s11010-024-05041-w
Essays Biochem. 2024 May 30. pii: EBC20230087. [Epub ahead of print]

Insights into the regulation of malate dehydrogenase: inhibitors, activators, and allosteric modulation by small molecules.

Betsy M Martinez-Vaz, Alicia L Howard, Varuni K Jamburuthugoda, Kevin P Callahan.

  Cellular metabolism comprises a complex network of biochemical anabolic and catabolic processes that fuel the growth and survival of living organisms. The enzyme malate dehydrogenase (MDH) is most known for its role in oxidizing malate to oxaloacetate (OAA) in the last step of the tricarboxylic acid (TCA) cycle, but it also participates in the malate-aspartate shuttle in the mitochondria as well as the glyoxylate cycle in plants. These pathways and the specific reactions within them are dynamic and must be carefully calibrated to ensure a balance between nutrient/energy supply and demand. MDH structural and functional complexity requires a variety of regulatory mechanisms, including allosteric regulation, feedback, and competitive inhibition, which are often dependent on whether the enzyme is catalyzing its forward or reverse reaction. Given the role of MDH in central metabolism and its potential as a target for therapeutics in both cancer and infectious diseases, there is a need to better understand its regulation. The involvement of MDH in multiple pathways makes it challenging to identify which effectors are critical to its activity. Many of the in vitro experiments examining MDH regulation were done decades ago, and though allosteric sites have been proposed, none to date have been specifically mapped. This review aims to provide an overview of the current knowledge surrounding MDH regulation by its substrate, products, and other intermediates of the TCA cycle while highlighting all the gaps in our understanding of its regulatory mechanisms.

Keywords:  Malate; activators; allosteric regulation; dehydrogenase; inhibitors; regulation

DOI:  https://doi.org/10.1042/EBC20230087