bims-glucam 2022-01-16 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2022–01–16
seventeen papers selected by
Sreeparna Banerjee, Middle East Technical University

High-resolution structures of mitochondrial glutaminase C tetramers indicate conformational changes upon phosphate binding.
Glutamine-Derived Aspartate Biosynthesis in Cancer Cells: Role of Mitochondrial Transporters and New Therapeutic Perspectives.
The mTOR/PGC-1α/SIRT3 Pathway Drives Reductive Glutamine Metabolism to Reduce Oxidative Stress Caused by ISKNV in CPB Cells.
Long noncoding RNA UCA1 promotes glutamine-driven anaplerosis of bladder cancer by interacting with hnRNP I/L to upregulate GPT2 expression.
Translational Activation of ATF4 through Mitochondrial Anaplerotic Metabolic Pathways Is Required for DLBCL Growth and Survival.
Cancer metabolism and intervention therapy.
Ionizing Radiation Upregulates Glutamine Metabolism and Induces Cell Death via Accumulation of Reactive Oxygen Species.
A biomimetic ZIF nanoagent for synergistic regulation of glutamine metabolism and intracellular acidosis of cancer.
Amino Acid Metabolism in Cancer Drug Resistance.
Loss of SDHB Induces a Metabolic Switch in the hPheo1 Cell Line toward Enhanced OXPHOS.
Interplay Among Metabolism, Epigenetic Modifications, and Gene Expression in Cancer.
Development of Nanocarrier-Based Mitochondrial Chaperone, TRAP-1 Inhibitor to Combat Cancer Metabolism.
Glutaminolysis is required in maintaining immune regulatory functions in B cells.
The role of m6A RNA methylation in cancer metabolism.
Systemically Applicable Glutamine-Functionalized Polymer Exerting Multivalent Interaction with Tumors Overexpressing ASCT2.
Maternal regulation of biliary disease in neonates via gut microbial metabolites.
Trans cohort metabolic reprogramming towards glutaminolysis in long-term successfully treated HIV-infection.

J Biol Chem. 2022 Jan 06. pii: S0021-9258(22)00004-7. [Epub ahead of print] 101564

High-resolution structures of mitochondrial glutaminase C tetramers indicate conformational changes upon phosphate binding.

Thuy-Tien T Nguyen, Sekar Ramachandran, Matthew J Hill, Richard A Cerione.

  The mitochondrial enzyme glutaminase C (GAC) is upregulated in many cancer cells to catalyze the first step in glutamine metabolism, the hydrolysis of glutamine to glutamate. The dependence of cancer cells on this transformed metabolic pathway highlights GAC as a potentially important therapeutic target. GAC acquires maximal catalytic activity upon binding to anionic activators such as inorganic phosphate. To delineate the mechanism of GAC activation, we used the tryptophan substitution of tyrosine 466 in the catalytic site of the enzyme as a fluorescent reporter for glutamine binding in the presence and absence of phosphate. We show that in the absence of phosphate, glutamine binding to the Y466W GAC tetramer exhibits positive cooperativity. A high-resolution X-ray structure of tetrameric Y466W GAC bound to glutamine suggests that cooperativity in substrate binding is coupled to tyrosine 249, located at the edge of the catalytic site (i.e. the 'lid'), adopting two distinct conformations. In one dimer within the GAC tetramer, the lids are open and glutamine binds weakly, whereas, in the adjoining dimer, the lids are closed over the substrates, resulting in higher affinity interactions. When crystallized in the presence of glutamine and phosphate, all four subunits of the Y466W GAC tetramer exhibited bound glutamine with closed lids. Glutamine can bind with high affinity to each subunit, which subsequently undergo simultaneous catalysis. These findings explain how the regulated transitioning of GAC between different conformational states ensures maximal catalytic activity is reached in cancer cells only when an allosteric activator is available.

Keywords:  cancer biology; enzyme mechanism; glutaminase; mitochondrial metabolism; structure‐function

DOI:  https://doi.org/10.1016/j.jbc.2022.101564
Cancers (Basel). 2022 Jan 04. pii: 245. [Epub ahead of print]14(1):

Glutamine-Derived Aspartate Biosynthesis in Cancer Cells: Role of Mitochondrial Transporters and New Therapeutic Perspectives.

Ruggiero Gorgoglione, Valeria Impedovo, Christopher L Riley, Deborah Fratantonio, Stefano Tiziani, Luigi Palmieri, Vincenza Dolce, Giuseppe Fiermonte.

  Aspartate has a central role in cancer cell metabolism. Aspartate cytosolic availability is crucial for protein and nucleotide biosynthesis as well as for redox homeostasis. Since tumor cells display poor aspartate uptake from the external environment, most of the cellular pool of aspartate derives from mitochondrial catabolism of glutamine. At least four transporters are involved in this metabolic pathway: the glutamine (SLC1A5_var), the aspartate/glutamate (AGC), the aspartate/phosphate (uncoupling protein 2, UCP2), and the glutamate (GC) carriers, the last three belonging to the mitochondrial carrier family (MCF). The loss of one of these transporters causes a paucity of cytosolic aspartate and an arrest of cell proliferation in many different cancer types. The aim of this review is to clarify why different cancers have varying dependencies on metabolite transporters to support cytosolic glutamine-derived aspartate availability. Dissecting the precise metabolic routes that glutamine undergoes in specific tumor types is of upmost importance as it promises to unveil the best metabolic target for therapeutic intervention.

Keywords:  SLC1A5_var; UCP2; aspartate; aspartate/glutamate carrier; cancer; glutamate carrier; glutamine metabolism; mitochondrial carriers

DOI:  https://doi.org/10.3390/cancers14010245
Microbiol Spectr. 2022 Jan 12. e0231021

The mTOR/PGC-1α/SIRT3 Pathway Drives Reductive Glutamine Metabolism to Reduce Oxidative Stress Caused by ISKNV in CPB Cells.

Xiaozhe Fu, Kejin Li, Yinjie Niu, Qiang Lin, Hongru Liang, Xia Luo, Lihui Liu, Ningqiu Li.

  Under oxidative stress, viruses prefer glycolysis as an ATP source, and glutamine is required as an anaplerotic substrate to replenish the TCA cycle. Infectious spleen and kidney necrosis virus (ISKNV) induces reductive glutamine metabolism in the host cells. Here we report that ISKNV infection the increased NAD+/NADH ratio and the gene expression of glutaminase 1 (GLS1), glutamate dehydrogenase (GDH), and isocitrate dehydrogenase (IDH2) resulted in the phosphorylation and activation of mammalian target of rapamycin (mTOR) in CPB cells. Inhibition of mTOR signaling attenuates ISKNV-induced the upregulation of GLS1, GDH, and IDH2 genes expression, and exhibits significant antiviral activity. Moreover, the expression of silent information regulation 2 homolog 3 (SIRT3) in mRNA level is increased to enhance the reductive glutamine metabolism in ISKNV-infected cells. And those were verified by the expression levels of metabolic genes and the activities of metabolic enzymes in SIRT3-overexpressed or SIRT3-knocked down cells. Remarkably, activation of mTOR signaling upregulates the expression of the peroxisome proliferator-activated receptor γ coactivator-1α (PGC-1α) gene, leading to increased expression of SIRT3 and metabolic genes. These results indicate that mTOR signaling manipulates reductive glutamine metabolism in ISKNV-infected cells through PGC-1α-dependent regulation of SIRT3. Our findings reveal new insights on ISKNV-host interactions and will contribute new cellular targets to antiviral therapy. IMPORTANCE Infectious spleen and kidney necrosis virus (ISKNV) is the causative agent of farmed fish disease that has caused huge economic losses in fresh and marine fish aquaculture. The redox state of cells is shaped by virus into a favorable microenvironment for virus replication and proliferation. Our previous study demonstrated that ISKNV replication induced glutamine metabolism reprogramming, and it is necessary for the ISKNV multiplication. In this study, the mechanistic link between the mTOR/PGC-1α/SIRT3 pathway and reductive glutamine metabolism in the ISKNV-infected cells was provided, which will contribute new insights into the pathogenesis of ISKNV and antiviral treatment strategies.

Keywords:  ISKNV; PGC-1α; SIRT3; mTOR; reductive glutamine metabolism

DOI:  https://doi.org/10.1128/spectrum.02310-21
Transl Oncol. 2022 Jan 09. pii: S1936-5233(22)00002-X. [Epub ahead of print]17 101340

Long noncoding RNA UCA1 promotes glutamine-driven anaplerosis of bladder cancer by interacting with hnRNP I/L to upregulate GPT2 expression.

Hua Zhao, Wenjing Wu, Xu Li, Wei Chen.

  Long noncoding RNA urothelial cancer associated 1 (UCA1), initially identified in bladder cancer, is associated with multiple cellular processes, including metabolic reprogramming. However, its characteristics in the anaplerosis context of bladder cancer (BLCA) remain elusive. We identified UCA1 as a binding partner of heterogeneous nuclear ribonucleoproteins (hnRNPs) I and L, RNA-binding proteins (RBPs) with no previously known role in metabolic reprogramming. UCA1 and hnRNP I/L profoundly affected glycolysis, TCA cycle, glutaminolysis, and proliferation of BLCA. Importantly, UCA1 specifically bound to and facilitated the combination of hnRNP I/L to the promoter of glutamic pyruvate transaminase 2 (GPT2), an enzyme transferring glutamate to α-ketoglutarate, resulting in upregulated expression of GPT2 and enhanced glutamine-derived carbons in the TCA cycle. We also systematically confirmed the influence of UCA1 and hnRNP I/L on metabolism and proliferation via glutamine-driven anaplerosis in BLCA. Our study revealed the critical role of UCA1-mediated mechanisms involved in glutamine-driven anaplerosis and provided novel evidence that lncRNA regulates metabolic reprogramming in tumor cells.

Keywords:  Bladder cancer; Glutamine-driven anaplerosis; HnRNP; LncRNA UCA1; Metabolism

DOI:  https://doi.org/10.1016/j.tranon.2022.101340
Blood Cancer Discov. 2022 Jan;3(1): 50-65

Translational Activation of ATF4 through Mitochondrial Anaplerotic Metabolic Pathways Is Required for DLBCL Growth and Survival.

Meng Li, Matthew R Teater, Jun Young Hong, Noel R Park, Cihangir Duy, Hao Shen, Ling Wang, Zhengming Chen, Leandro Cerchietti, Shawn M Davidson, Hening Lin, Ari M Melnick.

Diffuse large B-cell lymphomas (DLBCL) are broadly dependent on anaplerotic metabolism regulated by mitochondrial SIRT3. Herein we find that translational upregulation of ATF4 is coupled with anaplerotic metabolism in DLBCLs due to nutrient deprivation caused by SIRT3 driving rapid flux of glutamine into the tricarboxylic acid (TCA) cycle. SIRT3 depletion led to ATF4 downregulation and cell death, which was rescued by ectopic ATF4 expression. Mechanistically, ATF4 translation is inhibited in SIRT3-deficient cells due to the increased pools of amino acids derived from compensatory autophagy and decreased glutamine consumption by the TCA cycle. Absence of ATF4 further aggravates this state through downregulation of its target genes, including genes for amino acid biosynthesis and import. Collectively, we identify a SIRT3-ATF4 axis required to maintain survival of DLBCL cells by enabling them to optimize amino acid uptake and utilization. Targeting ATF4 translation can potentiate the cytotoxic effect of SIRT3 inhibitor to DLBCL cells. SIGNIFICANCE: We discovered the link between SIRT3 and ATF4 in DLBCL cells, which connected lymphoma amino acid metabolism with ATF4 translation via metabolic stress signals. SIRT3-ATF4 axis is required in DLBCL cells regardless of subtype, which indicates a common metabolic vulnerability in DLBCLs and can serve as a therapeutic target.This article is highlighted in the In This Issue feature, p. 1.

DOI: https://doi.org/10.1158/2643-3230.BCD-20-0183
Mol Biomed. 2021 Feb 20. 2(1): 5

Cancer metabolism and intervention therapy.

Huakan Zhao, Yongsheng Li.

  Metabolic reprogramming with heterogeneity is a hallmark of cancer and is at the basis of malignant behaviors. It supports the proliferation and metastasis of tumor cells according to the low nutrition and hypoxic microenvironment. Tumor cells frantically grab energy sources (such as glucose, fatty acids, and glutamine) from different pathways to produce a variety of biomass to meet their material needs via enhanced synthetic pathways, including aerobic glycolysis, glutaminolysis, fatty acid synthesis (FAS), and pentose phosphate pathway (PPP). To survive from stress conditions (e.g., metastasis, irradiation, or chemotherapy), tumor cells have to reprogram their metabolism from biomass production towards the generation of abundant adenosine triphosphate (ATP) and antioxidants. In addition, cancer cells remodel the microenvironment through metabolites, promoting an immunosuppressive microenvironment. Herein, we discuss how the metabolism is reprogrammed in cancer cells and how the tumor microenvironment is educated via the metabolic products. We also highlight potential metabolic targets for cancer therapies.

Keywords:  Cancer; Heterogeneity; Metabolic reprogramming; Targeted therapy; Tumor microenvironment

DOI:  https://doi.org/10.1186/s43556-020-00012-1
Oxid Med Cell Longev. 2021 ;2021 5826932

Ionizing Radiation Upregulates Glutamine Metabolism and Induces Cell Death via Accumulation of Reactive Oxygen Species.

Pengfei Yang, Xiangxia Luo, Jin Li, Tianyi Zhang, Xiaoling Gao, Junrui Hua, Yonghong Li, Nan Ding, Jinpeng He, Yanan Zhang, Wenjun Wei, Jufang Wang, Heng Zhou.

Glutamine metabolism provides energy to tumor cells and also produces reactive oxygen species (ROS). Excessive accumulation of ROS can damage mitochondria and eventually lead to cell death. xCT (SLC7A11) is responsible for the synthesis of glutathione in order to neutralize ROS. In addition, mitophagy can remove damaged mitochondria to keep the cell alive. Ionizing radiation kills tumor cells by causing the accumulation of ROS, which subsequently induces nuclear DNA damage. With this in mind, we explored the mechanism of intracellular ROS accumulation induced by ionizing radiation and hypothesized new methods to enhance the effect of radiotherapy. We used MCF-7 breast cancer cells and HCT116 colorectal cancer cells in our study. The above-mentioned cells were irradiated with different doses of X-rays or carbon ions. Clone formation assays were used to detect cell proliferation, enzyme-linked immunosorbent assay (ELISA) detected ATP, and glutathione (GSH) production, while the expression of proteins was detected by Western blot and quantitative real-time PCR analysis. The production of ROS was detected by flow cytometry, and immunofluorescence was used to track mitophagy-related processes. Finally, BALB/C tumor-bearing nude mice were irradiated with X-rays in order to further explore the protein expression found in tumors with the use of immunohistochemistry. Ionizing radiation increased the protein expressions of ASCT2, GLS, and GLUD in order to upregulate the glutamine metabolic flux in tumor cells. This caused an increase in ATP secretion. Meanwhile, ionizing radiation inhibited the expression of the xCT (SLC7A11) protein and reduced the generation of glutathione, leading to excessive accumulation of intracellular ROS. The mitophagy inhibitor, or knockdown Parkin gene, is able to enhance the ionizing radiation-induced ROS production and increase nucleus DNA damage. This combined treatment can significantly improve the killing effect of radiation on tumor cells. We concluded that ionizing radiation could upregulate the glutamine metabolic flux and enhance ROS accumulation in mitochondria. Ionizing radiation also decreased the SLC7A11 expression, resulting in reduced GSH generation. Therefore, inhibition of mitophagy can increase ionizing radiation-induced cell death.

DOI: https://doi.org/10.1155/2021/5826932
Chem Commun (Camb). 2022 Jan 11.

A biomimetic ZIF nanoagent for synergistic regulation of glutamine metabolism and intracellular acidosis of cancer.

Mengzhen Wang, Fei Lu, Na Li, Wei Pan, Bo Tang.

A homotypic cancer cell membrane camouflaged zeolitic imidazolate framework (ZIF)-based nanoagent with co-loading of two inhibitors was developed, which could suppress the efflux of protons to induce intracellular acidic stress and down-regulate glutamine metabolism to reduce the energy supply. As a compensation, glycometabolism would be upregulated with simultaneous production of large amounts of lactic acid, which could in turn aggravate the acidosis and further realize a synergetic cancer treatment.

DOI: https://doi.org/10.1039/d1cc05903c
Cells. 2022 Jan 02. pii: 140. [Epub ahead of print]11(1):

Amino Acid Metabolism in Cancer Drug Resistance.

Hee-Chan Yoo, Jung-Min Han.

  Despite the numerous investigations on resistance mechanisms, drug resistance in cancer therapies still limits favorable outcomes in cancer patients. The complexities of the inherent characteristics of tumors, such as tumor heterogeneity and the complicated interaction within the tumor microenvironment, still hinder efforts to overcome drug resistance in cancer cells, requiring innovative approaches. In this review, we describe recent studies offering evidence for the essential roles of amino acid metabolism in driving drug resistance in cancer cells. Amino acids support cancer cells in counteracting therapies by maintaining redox homeostasis, sustaining biosynthetic processes, regulating epigenetic modification, and providing metabolic intermediates for energy generation. In addition, amino acid metabolism impacts anticancer immune responses, creating an immunosuppressive or immunoeffective microenvironment. A comprehensive understanding of amino acid metabolism as it relates to therapeutic resistance mechanisms will improve anticancer therapeutic strategies.

Keywords:  amino acids; cancer; drug resistance; immune response

DOI:  https://doi.org/10.3390/cells11010140
Int J Mol Sci. 2022 Jan 05. pii: 560. [Epub ahead of print]23(1):

Loss of SDHB Induces a Metabolic Switch in the hPheo1 Cell Line toward Enhanced OXPHOS.

Mouna Tabebi, Ravi Kumar Dutta, Camilla Skoglund, Peter Söderkvist, Oliver Gimm.

   BACKGROUND: Enzymes of tricarboxylic acid (TCA) have recently been recognized as tumor suppressors. Mutations in the SDHB subunit of succinate dehydrogenase (SDH) cause pheochromocytomas and paragangliomas (PCCs/PGLs) and predispose patients to malignant disease with poor prognosis.
METHODS: Using the human pheochromocytoma cell line (hPheo1), we knocked down SDHB gene expression using CRISPR-cas9 technology.
RESULTS: Microarray gene expression analysis showed that >500 differentially expressed gene targets, about 54%, were upregulated in response to SDHB knock down. Notably, genes involved in glycolysis, hypoxia, cell proliferation, and cell differentiation were up regulated, whereas genes involved in oxidative phosphorylation (OXPHOS) were downregulated. In vitro studies show that hPheo1 proliferation is not affected negatively and the cells that survive by shifting their metabolism to the use of glutamine as an alternative energy source and promote OXPHOS activity. Knock down of SDHB expression results in a significant increase in GLUD1 expression in hPheo1 cells cultured as monolayer or as 3D culture. Analysis of TCGA data confirms the enhancement of GLUD1 in SDHB mutated/low expressed PCCs/PGLs.
CONCLUSIONS: Our data suggest that the downregulation of SDHB in PCCs/PGLs results in increased GLUD1 expression and may represent a potential biomarker and therapeutic target in SDHB mutated tumors and SDHB loss of activity-dependent diseases.

Keywords:  GLUD1; OXPHOS; PCCs/PGLs; SDHB; glutamine; hPheo1

DOI:  https://doi.org/10.3390/ijms23010560
Front Cell Dev Biol. 2021 ;9 793428

Interplay Among Metabolism, Epigenetic Modifications, and Gene Expression in Cancer.

Miaomiao Huo, Jingyao Zhang, Wei Huang, Yan Wang.

  Epigenetic modifications and metabolism are two fundamental biological processes. During tumorigenesis and cancer development both epigenetic and metabolic alterations occur and are often intertwined together. Epigenetic modifications contribute to metabolic reprogramming by modifying the transcriptional regulation of metabolic enzymes, which is crucial for glucose metabolism, lipid metabolism, and amino acid metabolism. Metabolites provide substrates for epigenetic modifications, including histone modification (methylation, acetylation, and phosphorylation), DNA and RNA methylation and non-coding RNAs. Simultaneously, some metabolites can also serve as substrates for nonhistone post-translational modifications that have an impact on the development of tumors. And metabolic enzymes also regulate epigenetic modifications independent of their metabolites. In addition, metabolites produced by gut microbiota influence host metabolism. Understanding the crosstalk among metabolism, epigenetic modifications, and gene expression in cancer may help researchers explore the mechanisms of carcinogenesis and progression to metastasis, thereby provide strategies for the prevention and therapy of cancer. In this review, we summarize the progress in the understanding of the interactions between cancer metabolism and epigenetics.

Keywords:  clinical trails; epigenetic modifications; gut microbiota; metabolic enzymes; metabolic reprogramming

DOI:  https://doi.org/10.3389/fcell.2021.793428
ACS Appl Bio Mater. 2020 Jul 20. 3(7): 4188-4197

Development of Nanocarrier-Based Mitochondrial Chaperone, TRAP-1 Inhibitor to Combat Cancer Metabolism.

Vijayalakshmi Amash, Khanderao Paithankar, Shrikant Purushottam Dharaskar, Abirami Arunachalam, Sreedhar Amere Subbarao.

  Among human diseases, cancer has been in the frontlines of drug discovery and development. Despite having several decades of research efforts, therapeutic targeting of cancer is still challenging, which is due to the ability of cancer cells to adapt to the tumor microenvironment, exhibiting resistance to therapeutic drugs, and facilitated altered cancer metabolism. The small molecule inhibitors aimed at targeting a selective pathway are becoming void since cancer cells can activate alternate mechanisms. Despite broad acceptance of the Warburg effect, cellular energy metabolism, which determines the cell fate, is often overlooked for cancer treatment. We reported earlier that mitochondrial chaperone, TRAP-1 acts as a switch for activating the alternate cellular metabolism. Hence, we hypothesized that interfering with TRAP-1 inhibition can target the activation of alternative energy metabolism and sensitize tumor cells to existing chemotherapeutic drugs. We developed a nanocarrier where the iron oxide nanoparticles (IONs) were conjugated to Hsp90 inhibitor, geldanamycin (GA), and the mitochondria localization signal (MLS) peptide. We examined its effect against mitochondrial dynamics and metabolic status of human tumor cells. The synthesized nanocarrier exhibited both stability and target-specific activity and did not show nanoparticle-associated cytotoxicity. However, the nanocarrier treated cancer cells exhibited altered mitochondrial morphology and decreased cellular ATP levels suggesting that selective TRAP-1 targeting interferes with the altered energy metabolism. We present a nanoparticle-based TRAP-1 inhibitor to target tumor metabolism.

Keywords:  MLS peptide; TRAP-1; cancer; geldanamycin; iron oxide nanoparticles; mitochondrion

DOI:  https://doi.org/10.1021/acsabm.0c00268
Mucosal Immunol. 2022 Jan 10.

Glutaminolysis is required in maintaining immune regulatory functions in B cells.

Jiang-Qi Liu, Xiao-Rui Geng, Tian-Yong Hu, Li-Hua Mo, Xiang-Qian Luo, Shu-Yao Qiu, Da-Bo Liu, Zhi-Gang Liu, Jian-Bo Shao, Zhi-Qiang Liu, Ping-Chang Yang.

IL-10-expressing regulatory B cells (B10 cells) are dysfunctional in patients with many immune disorders. The underlying mechanism remains to be further elucidated. Glutamine is an essential nutrient for cell metabolism. This study aims to elucidate the role of glutaminolysis in maintaining the immune regulatory capacity in B10 cells. Peripheral blood samples were collected from 50 patients with allergic rhinitis and 50 healthy control subjects. B cells were isolated from blood samples by cell sorting with flow cytometry. The role of glutaminolysis in regulating B10 cell activities was assessed by immunological and biochemical approaches. The results showed that B cells from patients with allergic rhinitis expressed low levels of the transporter of glutamine and neutral amino acid. Glutaminolysis was required in the IL-10 expression in B cells. The glutamine catabolism was required in B10 cell generation. The mTOR activation mediated the glutaminolysis-associated B10 cell induction, and the suppression of the B cell glycogen synthase kinase-3 (GSK3) activation. GSK3 activation suppressed IL-10 expression in B cells. Inhibition of GSK3 enhanced IL-10 expression in B cells and alleviated experimental allergic rhinitis by generating immune competent type 1 regulatory T cells.

DOI: https://doi.org/10.1038/s41385-021-00481-9
Mol Cancer. 2022 Jan 12. 21(1): 14

The role of m6A RNA methylation in cancer metabolism.

Yuanyuan An, Hua Duan.

  Metabolic reprogramming is one of the main characteristics of malignant tumors, which is due to the flexible changes of cell metabolism that can meet the needs of cell growth and maintain the homeostasis of tissue environments. Cancer cells can obtain metabolic adaptation through a variety of endogenous and exogenous signaling pathways, which can not only promote the growth of malignant cancer cells, but also start the transformation process of cells to adapt to tumor microenvironment. Studies show that m6A RNA methylation is widely involved in the metabolic recombination of tumor cells. In eukaryotes, m6A methylation is the most abundant modification in mRNA, which is involved in almost all the RNA cycle stages, including regulation the transcription, maturation, translation, degradation and stability of mRNA. M6A RNA methylation can be involved in the regulation of physiological and pathological processes, including cancer. In this review, we discuss the role of m6A RNA methylation modification plays in tumor metabolism-related molecules and pathways, aiming to show the importance of targeting m6A in regulating tumor metabolism.

Keywords:  Cancer; Metabolism reprogramming; The m6A

DOI:  https://doi.org/10.1186/s12943-022-01500-4
ACS Appl Bio Mater. 2021 Oct 18. 4(10): 7402-7407

Systemically Applicable Glutamine-Functionalized Polymer Exerting Multivalent Interaction with Tumors Overexpressing ASCT2.

Yuto Honda, Takahiro Nomoto, Hiroyasu Takemoto, Makoto Matsui, Kaori Taniwaki, Haochen Guo, Yutaka Miura, Nobuhiro Nishiyama.

  Transporter ASCT2, which predominantly imports glutamine (Gln), is overexpressed in a variety of cancer cells, and targeting ASCT2 is expected to be a promising approach for tumor diagnosis and therapy. In this work, we designed a series of glutamine-modified poly(l-lysine) (PLys(Gln)) homopolymers and PEG-PLys(Gln) block copolymers and investigated their tumor-targeting abilities. With increasing degree of polymerization in the PLys(Gln) homopolymers, their cellular uptake was gradually enhanced through multivalent interactions with ASCT2. The performance of PEG-PLys(Gln) in blood circulation and tumor accumulation could be controlled by tuning of the molecular weight of PEG. Our results highlight the utility of molecular recognition in ASCT2/PLys(Gln) for tumor targeting through systemic administration.

Keywords:  drug delivery system; functional polymer; glutamine transporter; multivalent interaction; tumor-targeting

DOI:  https://doi.org/10.1021/acsabm.1c00771
Nat Commun. 2022 Jan 10. 13(1): 18

Maternal regulation of biliary disease in neonates via gut microbial metabolites.

Jai Junbae Jee, Li Yang, Pranavkumar Shivakumar, Pei-Pei Xu, Reena Mourya, Unmesha Thanekar, Pu Yu, Yu Zhu, Yongkang Pan, Haibin Wang, Xufei Duan, Yongqin Ye, Bin Wang, Zhu Jin, Yuanmei Liu, Zhiqing Cao, Miki Watanabe-Chailland, Lindsey E Romick-Rosendale, Michael Wagner, Lin Fei, Zhenhua Luo, Nicholas J Ollberding, Shao-Tao Tang, Jorge A Bezerra.

Maternal seeding of the microbiome in neonates promotes a long-lasting biological footprint, but how it impacts disease susceptibility in early life remains unknown. We hypothesized that feeding butyrate to pregnant mice influences the newborn's susceptibility to biliary atresia, a severe cholangiopathy of neonates. Here, we show that butyrate administration to mothers renders newborn mice resistant to inflammation and injury of bile ducts and improves survival. The prevention of hepatic immune cell activation and survival trait is linked to fecal signatures of Bacteroidetes and Clostridia and increases glutamate/glutamine and hypoxanthine in stool metabolites of newborn mice. In human neonates with biliary atresia, the fecal microbiome signature of these bacteria is under-represented, with suppression of glutamate/glutamine and increased hypoxanthine pathways. The direct administration of butyrate or glutamine to newborn mice attenuates the disease phenotype, but only glutamine renders bile duct epithelial cells resistant to cytotoxicity by natural killer cells. Thus, maternal intake of butyrate influences the fecal microbial population and metabolites in newborn mice and the phenotypic expression of experimental biliary atresia, with glutamine promoting survival of bile duct epithelial cells.

DOI: https://doi.org/10.1038/s41467-021-27689-4
Commun Biol. 2022 Jan 11. 5(1): 27

Trans cohort metabolic reprogramming towards glutaminolysis in long-term successfully treated HIV-infection.

Flora Mikaeloff, Sara Svensson Akusjärvi, George Mondinde Ikomey, Shuba Krishnan, Maike Sperk, Soham Gupta, Gustavo Daniel Vega Magdaleno, Alejandra Escós, Emilia Lyonga, Marie Claire Okomo, Claude Tayou Tagne, Hemalatha Babu, Christian L Lorson, Ákos Végvári, Akhil C Banerjea, Julianna Kele, Luke Elizabeth Hanna, Kamal Singh, João Pedro de Magalhães, Rui Benfeitas, Ujjwal Neogi.

Despite successful combination antiretroviral therapy (cART), persistent low-grade immune activation together with inflammation and toxic antiretroviral drugs can lead to long-lasting metabolic flexibility and adaptation in people living with HIV (PLWH). Our study investigated alterations in the plasma metabolic profiles by comparing PLWH on long-term cART(>5 years) and matched HIV-negative controls (HC) in two cohorts from low- and middle-income countries (LMIC), Cameroon, and India, respectively, to understand the system-level dysregulation in HIV-infection. Using untargeted and targeted LC-MS/MS-based metabolic profiling and applying advanced system biology methods, an altered amino acid metabolism, more specifically to glutaminolysis in PLWH than HC were reported. A significantly lower level of neurosteroids was observed in both cohorts and could potentiate neurological impairments in PLWH. Further, modulation of cellular glutaminolysis promoted increased cell death and latency reversal in pre-monocytic HIV-1 latent cell model U1, which may be essential for the clearance of the inducible reservoir in HIV-integrated cells.

DOI: https://doi.org/10.1038/s42003-021-02985-3