bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2023–03–05
eleven papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Glutamine metabolism in breast cancer and possible therapeutic targets.
  2. A photodynamic-mediated glutamine metabolic intervention nanodrug for triple negative breast cancer therapy.
  3. Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis.
  4. Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: Clinical efficacy and correlative analyses.
  5. HPV16 E6 and E7 Oncoproteins Stimulate the Glutamine Pathway Maintaining Cell Proliferation in a SNAT1-Dependent Fashion.
  6. Integrating single-cell RNA-seq and bulk RNA-seq to construct prognostic signatures to explore the role of glutamine metabolism in breast cancer.
  7. Metabolic Rewiring and Stemness: A Critical attribute of Pancreatic Cancer Progression.
  8. What is cancer metabolism?
  9. Comprehensive Metabolic Tracing Reveals the Origin and Catabolism of Cysteine in Mammalian Tissues and Tumors.
  10. Editorial: Targeting metabolism of cancer cells and host to overcome drug resistance: Preclinical and clinical studies.
  11. NRF2 activation induces NADH-reductive stress, providing a metabolic vulnerability in lung cancer.
  1. Biochem Pharmacol. 2023 Feb 25. pii: S0006-2952(23)00055-2. [Epub ahead of print] 115464
    Glutamine metabolism in breast cancer and possible therapeutic targets.
    Shiqi Li, Hui Zeng, Junli Fan, Fubing Wang, Chen Xu, Yirong Li, Jiancheng Tu, Kenneth P Nephew, Xinghua Long.
      Cancer is characterized by metabolic reprogramming, which is a hot topic in tumor treatment research. Cancer cells alter metabolic pathways to promote their growth, and the common purpose of these altered metabolic pathways is to adapt the metabolic state to the uncontrolled proliferation of cancer cells. Most cancer cells in a state of nonhypoxia will increase the uptake of glucose and produce lactate, called the Warburg effect. Increased glucose consumption is used as a carbon source to support cell proliferation, including nucleotide, lipid and protein synthesis. In the Warburg effect, pyruvate dehydrogenase activity decreases, thereby disrupting the TCA cycle. In addition to glucose, glutamine is also an important nutrient for the growth and proliferation of cancer cells, an important carbon bank and nitrogen bank for the growth and proliferation of cancer cells, providing ribose, nonessential amino acids, citrate, and glycerin necessary for cancer cell growth and proliferation and compensating for the reduction in oxidative phosphorylation pathways in cancer cells caused by the Warburg effect. In human plasma, glutamine is the most abundant amino acid. Normal cells produce glutamine via glutamine synthase (GLS), but the glutamine synthesized by tumor cells is insufficient to meet their high growth needs, resulting in a "glutamine-dependent phenomenon." Most cancers have an increased glutamine demand, including breast cancer. Metabolic reprogramming not only enables tumor cells to maintain the reduction-oxidation (redox) balance and commit resources to biosynthesis but also establishes heterogeneous metabolic phenotypes of tumor cells that are distinct from those of nontumor cells. Thus, targeting the metabolic differences between tumor and nontumor cells may be a promising and novel anticancer strategy. Glutamine metabolic compartments have emerged as promising candidates, especially in TNBC and drug-resistant breast cancer. In this review, the latest discoveries of breast cancer and glutamine metabolism are discussed, novel treatment methods based on amino acid transporters and glutaminase are discussed, and the relationship between glutamine metabolism and breast cancer metastasis, drug resistance, tumor immunity and ferroptosis are explained, which provides new ideas for the clinical treatment of breast cancer.
    Keywords:  Amino acid transporters; Breast cancer; Glutaminase; Glutamine metabolism; Immune microenvironment; ferroptosis
    DOI:  https://doi.org/10.1016/j.bcp.2023.115464
  2. Mater Today Bio. 2023 Apr;19 100577
    A photodynamic-mediated glutamine metabolic intervention nanodrug for triple negative breast cancer therapy.
    Cancan Yu, Ningning Wang, Xiangwu Chen, Yue Jiang, Yuxia Luan, Wen Qin, Wenxiu He.
      "Glutamine addiction" is a unique feature of triple negative breast cancer (TNBC), which has a higher demand for glutamine and is more susceptible to glutamine depletion. Glutamine can be hydrolyzed to glutamate by glutaminase (GLS) for synthesis of glutathione (GSH), which is an important downstream of glutamine metabolic pathways in accelerating TNBC proliferation. Consequently, glutamine metabolic intervention suggests potential therapeutic effects against TNBC. However, the effects of GLS inhibitors are hindered by glutamine resistance and their own instability and insolubility. Therefore, it is of great interest to harmonize glutamine metabolic intervention for an amplified TNBC therapy. Unfortunately, such nanoplatform has not been realized. Herein, we reported a self-assembly nanoplatform (BCH NPs) with a core of the GLS inhibitor Bis-2-(5-phenylacetamido-1,3,4-thiadiazol-2-yl) ethyl sulfide (BPTES) and photosensitizer Chlorin e6 (Ce6) and a shell of human serum albumin (HSA), enabling effective harmonization of glutamine metabolic intervention for TNBC therapy. BPTES inhibited the activity of GLS to block the glutamine metabolic pathways, thereby inhibiting the production of GSH to amplify the photodynamic effect of Ce6. While Ce6 not only directly killed tumor cells by producing excessive reactive oxygen species (ROS), but also deplete GSH to destroy redox balance, thus enhancing the effects of BPTES when glutamine resistance occurred. BCH NPs effectively eradicated TNBC tumor and suppressed tumor metastasis with favorable biocompatibility. Our work provides a new insight for photodynamic-mediated glutamine metabolic intervention against TNBC.
    Keywords:  BPTES; Ce6; Glutamine metabolic intervention; Photodynamic therapy; Triple negative breast cancer
    DOI:  https://doi.org/10.1016/j.mtbio.2023.100577
  3. bioRxiv. 2023 Feb 23. pii: 2023.02.23.529704. [Epub ahead of print]
    Glutamine metabolism inhibition has dual immunomodulatory and antibacterial activities against Mycobacterium tuberculosis.
    Sadiya Parveen, Jessica Shen, Shichun Lun, Liang Zhao, Benjamin Koleske, Robert D Leone, Rana Rais, Jonathan D Powell, John R Murphy, Barbara S Slusher, William R Bishai.
      As one of the most successful human pathogens, Mycobacterium tuberculosis ( Mtb ) has evolved a diverse array of determinants to subvert host immunity and alter host metabolic patterns. However, the mechanisms of pathogen interference with host metabolism remain poorly understood. Here we show that a novel glutamine metabolism antagonist, JHU083, inhibits Mtb proliferation in vitro and in vivo. JHU083-treated mice exhibit weight gain, improved survival, a 2.5 log lower lung bacillary burden at 35 days post-infection, and reduced lung pathology. JHU083 treatment also initiates earlier T-cell recruitment, increased proinflammatory myeloid cell infiltration, and a reduced frequency of immunosuppressive myeloid cells when compared to uninfected and rifampin-treated controls. Metabolomics analysis of lungs from JHU083-treated Mtb -infected mice revealed reduced glutamine levels, citrulline accumulation suggesting elevated NOS activity, and lowered levels of quinolinic acid which is derived from the immunosuppressive metabolite kynurenine. When tested in an immunocompromised mouse model of Mtb infection, JHU083 lost its therapeutic efficacy suggesting the drug’s host-directed effects are likely to be predominant. Collectively, these data reveal that JHU083-mediated glutamine metabolism inhibition results in dual antibacterial and host-directed activity against tuberculosis.
    DOI:  https://doi.org/10.1101/2023.02.23.529704
  4. Res Sq. 2023 Feb 23. pii: rs.3.rs-2518774. [Epub ahead of print]
    Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: Clinical efficacy and correlative analyses.
    Marina Konopleva, Courtney DiNardo, Tushar Bhagat, Natalia Baran, Alessia Lodi, Kapil Saxena, Tianyu Cai, Xiaoping Su, Anna Skwarska, Veronica Guerra, Vinitha Kuruvilla, Sergej Konoplev, Shanisha Gordon-Mitchell, Kith Pradhan, Srinivas Aluri, Meghan Collins, Shannon Sweeney, Jonathan Busquet, Atul Rathore, Qing Deng, Michael Green, Steven Grant, Susan Demo, Gaurav Choudhary, Srabani Sahu, Beamon Agarwal, Mason Spodek, Victor Thiruthuvanathan, Britta Will, Ulrich Steidl, George Tippett, Jan Burger, Gautam Borthakur, Elias Jabbour, Naveen Pemmaraju, Tapan Kadia, Steven Kornblau, Naval Daver, Kiran Naqvi, Nicholas Short, Guillermo Garcia-Manero, Stefano Tiziani, Amit Verma.
      Malignancies can become reliant on glutamine as an alternative energy source and as a facilitator of aberrant DNA methylation, thus implicating glutaminase (GLS) as a potential therapeutic target. We demonstrate preclinical synergy of telaglenastat (CB-839), a selective GLS inhibitor, when combined with azacytidine (AZA), in vitro and in vivo , followed by a phase Ib/II study of the combination in patients with advanced MDS. Treatment with telaglenastat/AZA led to an ORR of 70% with CR/mCRs in 53% patients and a median overall survival of 11.6 months. scRNAseq and flow cytometry demonstrated a myeloid differentiation program at the stem cell level in clinical responders. Expression of non-canonical glutamine transporter, SLC38A1, was found to be overexpressed in MDS stem cells; was associated with clinical responses to telaglenastat/AZA and predictive of worse prognosis in a large MDS cohort. These data demonstrate the safety and efficacy of a combined metabolic and epigenetic approach in MDS.
    DOI:  https://doi.org/10.21203/rs.3.rs-2518774/v1
  5. Viruses. 2023 Jan 24. pii: 324. [Epub ahead of print]15(2):
    HPV16 E6 and E7 Oncoproteins Stimulate the Glutamine Pathway Maintaining Cell Proliferation in a SNAT1-Dependent Fashion.
    Yunuen Ortiz-Pedraza, J Omar Muñoz-Bello, Lucio Antonio Ramos-Chávez, Imelda Martínez-Ramírez, Leslie Olmedo-Nieva, Joaquín Manzo-Merino, Alejandro López-Saavedra, Verónica Pérez-de la Cruz, Marcela Lizano.
      Persistent high-risk human papillomavirus infection is the main risk factor for cervical cancer establishment, where the viral oncogenes E6 and E7 promote a cancerous phenotype. Metabolic reprogramming in cancer involves alterations in glutamine metabolism, also named glutaminolysis, to provide energy for supporting cancer processes including migration, proliferation, and production of reactive oxygen species, among others. The aim of this work was to analyze the effect of HPV16 E6 and E7 oncoproteins on the regulation of glutaminolysis and its contribution to cell proliferation. We found that the E6 and E7 oncoproteins exacerbate cell proliferation in a glutamine-dependent manner. Both oncoproteins increased the levels of transporter SNAT1, as well as GLS2 and GS enzymes; E6 also increased LAT1 transporter protein levels, while E7 increased ASCT2 and xCT. Some of these alterations are also regulated at a transcriptional level. Consistently, the amount of SNAT1 protein decreased in Ca Ski cells when E6 and E7 expression was knocked down. In addition, we demonstrated that cell proliferation was partially dependent on SNAT1 in the presence of glutamine. Interestingly, SNAT1 expression was higher in cervical cancer compared with normal cervical cells. The high expression of SNAT1 was associated with poor overall survival of cervical cancer patients. Our results indicate that HPV oncoproteins exacerbate glutaminolysis supporting the malignant phenotype.
    Keywords:  HPV16 E6 and E7 oncoproteins; SNAT1 transporter; glutaminolysis
    DOI:  https://doi.org/10.3390/v15020324
  6. Front Endocrinol (Lausanne). 2023 ;14 1135297
    Integrating single-cell RNA-seq and bulk RNA-seq to construct prognostic signatures to explore the role of glutamine metabolism in breast cancer.
    Shengbin Pei, Pengpeng Zhang, Huilin Chen, Shuhan Zhao, Yuhan Dai, Lili Yang, Yakun Kang, Mingjie Zheng, Yiqin Xia, Hui Xie.
       Background: Although breast cancer (BC) treatment has entered the era of precision therapy, the prognosis is good in the case of comprehensive multimodal treatment such as neoadjuvant, endocrine, and targeted therapy. However, due to its high heterogeneity, some patients still cannot benefit from conventional treatment and have poor survival prognoses. Amino acids and their metabolites affect tumor development, alter the tumor microenvironment, play an increasingly obvious role in immune response and regulation of immune cell function, and are involved in acquired and innate immune regulation; therefore, amino acid metabolism is receiving increasing attention.
    Methods: Based on public datasets, we carried out a comprehensive transcriptome and single-cell sequencing investigation. Then we used 2.5 Weighted Co-Expression Network Analysis (WGCNA) and Cox to evaluate glutamine metabolism-related genes (GRGs) in BC and constructed a prognostic model for BC patients. Finally, the expression and function of the signature key gene SNX3 were examined by in vitro experiments.
    Results: In this study, we constituted a risk signature to predict overall survival (OS) in BC patients by glutamine-related genes. According to our risk signature, BC patients can obtain a Prognostic Risk Signature (PRS), and the response to immunotherapy can be further stratified according to PRS. Compared with traditional clinicopathological features, PRS demonstrated robust prognostic power and accurate survival prediction. In addition, altered pathways and mutational patterns were analyzed in PRS subgroups. Our study sheds some light on the immune status of BC. In in vitro experiments, the knockdown of SNX3, an essential gene in the signature, resulted in a dramatic reduction in proliferation, invasion, and migration of MDA-MB-231 and MCF-7 cell lines.
    Conclusion: We established a brand-new PRS consisting of genes associated with glutamine metabolism. It expands unique ideas for the diagnosis, treatment, and prognosis of BC.
    Keywords:  SNX3; breast cancer; glutamine; metabolism; single-cell sequencing
    DOI:  https://doi.org/10.3389/fendo.2023.1135297
  7. Stem Cells. 2023 Mar 04. pii: sxad017. [Epub ahead of print]
    Metabolic Rewiring and Stemness: A Critical attribute of Pancreatic Cancer Progression.
    Ayoola O Ogunleye, Rama Krishna Nimmakayala, Surinder K Batra, Moorthy P Ponnusamy.
      Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive diseases with a poor 5-year survival rate. PDAC cells rely on various metabolic pathways to fuel their unlimited proliferation and metastasis. Reprogramming glucose, fatty acid, amino acid, and nucleic acid metabolisms contributes to PDAC cell growth. Cancer stem cells are the primary cell types that play a critical role in the progression and aggressiveness of PDAC. Emerging studies indicate that the cancer stem cells in PDAC tumors are heterogeneous and show specific metabolic dependencies. In addition, understanding specific metabolic signatures and factors that regulate these metabolic alterations in the cancer stem cells of PDAC paves the way for developing novel therapeutic strategies targeting CSCs. In this review, we discuss the current understanding of PDAC metabolism by specifically exploring the metabolic dependencies of cancer stem cells. We also review the current knowledge of targeting these metabolic factors that regulate CSC maintenance and PDAC progression.
    Keywords:  Pancreatic cancer; cancer stem cells; metabolism; targeting metabolic pathways
    DOI:  https://doi.org/10.1093/stmcls/sxad017
  8. Cell. 2023 Feb 22. pii: S0092-8674(23)00097-1. [Epub ahead of print]
    What is cancer metabolism?
    Lydia W S Finley.
      The uptake and metabolism of nutrients support fundamental cellular process from bioenergetics to biomass production and cell fate regulation. While many studies of cell metabolism focus on cancer cells, the principles of metabolism elucidated in cancer cells apply to a wide range of mammalian cells. The goal of this review is to discuss how the field of cancer metabolism provides a framework for revealing principles of cell metabolism and for dissecting the metabolic networks that allow cells to meet their specific demands. Understanding context-specific metabolic preferences and liabilities will unlock new approaches to target cancer cells to improve patient care.
    DOI:  https://doi.org/10.1016/j.cell.2023.01.038
  9. Cancer Res. 2023 Mar 02. pii: CAN-22-3000. [Epub ahead of print]
    Comprehensive Metabolic Tracing Reveals the Origin and Catabolism of Cysteine in Mammalian Tissues and Tumors.
    Sang Jun Yoon, Joseph A Combs, Aimee Falzone, Nicolas Prieto-Farigua, Samantha Caldwell, Hayley D Ackerman, Elsa R Flores, Gina M DeNicola.
      Cysteine plays critical roles in cellular biosynthesis, enzyme catalysis, and redox metabolism. The intracellular cysteine pool can be sustained by cystine uptake or de novo synthesis from serine and homocysteine. Demand for cysteine is increased during tumorigenesis for generating glutathione to deal with oxidative stress. While cultured cells have been shown to be highly dependent on exogenous cystine for proliferation and survival, how diverse tissues obtain and use cysteine in vivo has not been characterized. We comprehensively interrogated cysteine metabolism in normal murine tissues and cancers that arise from them using stable isotope 13C1-serine and 13C6-cystine tracing. De novo cysteine synthesis was highest in normal liver and pancreas and absent in lung tissue, while cysteine synthesis was either inactive or downregulated during tumorigenesis. By contrast, cystine uptake and metabolism to downstream metabolites was a universal feature of normal tissues and tumors. However, differences in glutathione labeling from cysteine were evident across tumor types. Thus, cystine is a major contributor to the cysteine pool in tumors, and glutathione metabolism is differentially active across tumor types.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-22-3000
  10. Front Oncol. 2023 ;13 1154661
    Editorial: Targeting metabolism of cancer cells and host to overcome drug resistance: Preclinical and clinical studies.
    Lishun Wang, Hanchen Xu, Yadi Wu.
      
    Keywords:  cancer metabolism; drug resistance; gut microbiome; metabolite; omics
    DOI:  https://doi.org/10.3389/fonc.2023.1154661
  11. Cell Metab. 2023 Feb 22. pii: S1550-4131(23)00012-8. [Epub ahead of print]
    NRF2 activation induces NADH-reductive stress, providing a metabolic vulnerability in lung cancer.
    Tommy Weiss-Sadan, Maolin Ge, Makiko Hayashi, Magdy Gohar, Cong-Hui Yao, Adriaan de Groot, Stefan Harry, Alexander Carlin, Hannah Fischer, Lei Shi, Ting-Yu Wei, Charles H Adelmann, Konstantin Wolf, Tristan Vornbäumen, Benedikt R Dürr, Mariko Takahashi, Marianne Richter, Junbing Zhang, Tzu-Yi Yang, Vindhya Vijay, David E Fisher, Aaron N Hata, Marcia C Haigis, Raul Mostoslavsky, Nabeel Bardeesy, Thales Papagiannakopoulos, Liron Bar-Peled.
      Multiple cancers regulate oxidative stress by activating the transcription factor NRF2 through mutation of its negative regulator, KEAP1. NRF2 has been studied extensively in KEAP1-mutant cancers; however, the role of this pathway in cancers with wild-type KEAP1 remains poorly understood. To answer this question, we induced NRF2 via pharmacological inactivation of KEAP1 in a panel of 50+ non-small cell lung cancer cell lines. Unexpectedly, marked decreases in viability were observed in >13% of the cell lines-an effect that was rescued by NRF2 ablation. Genome-wide and targeted CRISPR screens revealed that NRF2 induces NADH-reductive stress, through the upregulation of the NAD+-consuming enzyme ALDH3A1. Leveraging these findings, we show that cells treated with KEAP1 inhibitors or those with endogenous KEAP1 mutations are selectively vulnerable to Complex I inhibition, which impairs NADH oxidation capacity and potentiates reductive stress. Thus, we identify reductive stress as a metabolic vulnerability in NRF2-activated lung cancers.
    Keywords:  NADH/NAD(+); NRF2-KEAP1 pathway; functional genomic; non-small cell lung cancer; oxidative phosphorylation; reductive stress
    DOI:  https://doi.org/10.1016/j.cmet.2023.01.012
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