bims-glucam 2023-04-16 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2023–04–16
eleven papers selected by
Sreeparna Banerjee, Middle East Technical University

Metabolic dependencies and targets in ovarian cancer.
Targeting cancer metabolic vulnerabilities for advanced therapeutic efficacy.
Glutaminase 1 isoform up-regulation associated with lipid metabolism disorder induced by methyl tertiary-butyl ether in male rats.
PASK links cellular energy metabolism with a mitotic self-renewal network to establish differentiation competence.
Lipid Metabolic Reprogramming in Embryonal Neoplasms with MYCN Amplification.
Single-cell RNA sequencing reveals XBP1-SLC38A2 axis as a metabolic regulator in cytotoxic T lymphocytes in multiple myeloma.
Amino acids in hematologic malignancies: Current status and future perspective.
Phenotypic plasticity and reduced tissue retention of exhausted tumor-infiltrating T cells following neoadjuvant immunotherapy in head and neck cancer.
Emerging role of substance and energy metabolism associated with neuroendocrine regulation in tumor cells.
The combination of immunotherapy and a glutamine metabolism inhibitor represents an effective therapeutic strategy for advanced and metastatic murine pancreatic adenocarcinoma.
The Interaction between Gut Microbiota and Host Amino Acids Metabolism in Multiple Myeloma.

Pharmacol Ther. 2023 Apr 12. pii: S0163-7258(23)00077-3. [Epub ahead of print] 108413

Metabolic dependencies and targets in ovarian cancer.

Yaqi Zhang, Yinu Wang, Guangyuan Zhao, Sandra Orsulic, Daniela Matei.

  Reprogramming of cellular metabolism is a hallmark of cancer. Cancer cells undergo metabolic adaptations to maintain tumorigenicity and survive under the attack of immune cells and chemotherapy in the tumor microenvironment. Metabolic alterations in ovarian cancer in part overlap with findings from other solid tumors and in part reflect unique traits. Altered metabolic pathways not only facilitate ovarian cancer cells' survival and proliferation but also endow them to metastasize, acquire resistance to chemotherapy, maintain cancer stem cell phenotype and escape the effects of anti-tumor immune defense. In this review, we comprehensively review the metabolic signatures of ovarian cancer and their impact on cancer initiation, progression, and resistance to treatment. We highlight novel therapeutic strategies targeting metabolic pathways under development.

Keywords:  Endoplasmic reticulum stress; Glutamine; Glycolysis; Lipids; Metabolism; Ovarian cancer; Oxidative phosphorylation; Reactive oxygen species

DOI:  https://doi.org/10.1016/j.pharmthera.2023.108413
Biomed Pharmacother. 2023 Apr 07. pii: S0753-3322(23)00446-8. [Epub ahead of print]162 114658

Targeting cancer metabolic vulnerabilities for advanced therapeutic efficacy.

Tobias Achu Muluh, Xing-Sheng Shu, Ying Ying.

  Cancer metabolism is how cancer cells utilize nutrients and energy to support their growth and proliferation. Unlike normal cells, cancer cells have a unique metabolic profile that allows them to generate energy and the building blocks they need for rapid growth and division. This metabolic profile is marked by an increased reliance on glucose and glutamine as energy sources and changes in how cancer cells use and make key metabolic intermediates like ATP, NADH, and NADPH. This script analyzes a comprehensive overview of the latest advances in tumor metabolism, identifying the key unresolved issues, elaborates on how tumor cells differ from normal cells in their metabolism of nutrients, and explains how tumor cells conflate growth signals and nutrients to proliferate. The metabolic interaction of tumorigenesis and lipid metabolism within the tumor microenvironment and the role of ROS as an anti-tumor agent by mediating various signaling pathways for clinical cancer therapeutic targeting are outlined. Cancer metabolism is highly dynamic and heterogeneous; thus, advanced technologies to better investigate metabolism at the unicellular level without altering tumor tissue are necessary for better research and clinical transformation. The study of cancer metabolism is an area of active research, as scientists seek to understand the underlying metabolic changes that drive cancer growth and to identify potential therapeutic targets.

Keywords:  Cancer metabolism; Lipid metabolism; Metabolic reprogramming and Pathways; Reactive oxygen species; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.biopha.2023.114658
Ecotoxicol Environ Saf. 2023 Apr 15. pii: S0147-6513(23)00267-1. [Epub ahead of print]255 114763

Glutaminase 1 isoform up-regulation associated with lipid metabolism disorder induced by methyl tertiary-butyl ether in male rats.

Mingxiao Guo, Mengdi Li, Li Chen, Hanyun Wang, Jiajia Wang, Piye Niu, Junxiang Ma.

  Methyl tertiary-butyl ether (MTBE) is a new unleaded gasoline additive, which is considered to be associated with abnormal lipid metabolism in many studies, but the metabolic characteristics and mechanism are still unclear. To observe the characteristics of lipid metabolism induced by MTBE and possible pathways, 21 male Wistar rats got intragastric administration for 24 weeks. The serum lipid metabolism indexes and metabolites were analyzed separately by a biochemical analyzer and untargeted metabolomics. And found that serum high-density lipoprotein cholesterol (HDL-C) levels in the exposure group were significantly reduced, and serum very low-density lipoprotein (VLDL) levels were significantly increased. In untargeted metabolomics, 190 differential metabolites were obtained. Among them, 23 metabolites were found to show the same trend in MTBE exposure groups, which might play a key role in systemic energy metabolism. Further metabolic pathways analysis showed that D-Glutamine, D-glutamate metabolism, and the other three pathways were affected by MTBE significantly. Therefore, we evaluated serum glutamine and glutamate levels and found that MTBE exposure significantly reduced glutamine levels and increased glutamate levels in rat serum and L-02 cells. Further, the key regulatory gene of glutamine metabolism, glutaminase 1 isoform (GLS1), was significantly up-regulated in rat liver and L-02 cells exposed to MTBE. While the effect of glutamine and glutamate metabolism induced by MTBE could be weakened by BPTES, an antagonist of GLS1. In conclusion, our results indicated that MTBE exposure could change the level of glutamine metabolism by promoting GLS1 expression and ultimately lead to abnormal lipid metabolism.

Keywords:  Disorder of lipid metabolism; Glutamate; Glutaminase 1 isoform (GLS1); Glutamine; Metabolomics; Methyl tertiary-butyl ether (MTBE)

DOI:  https://doi.org/10.1016/j.ecoenv.2023.114763
Elife. 2023 Apr 13. pii: e81717. [Epub ahead of print]12

PASK links cellular energy metabolism with a mitotic self-renewal network to establish differentiation competence.

Michael Xiao, Chia-Hua Wu, Graham Meek, Brian Kelly, Dara Buendia Castillo, Lyndsay E A Young, Sara Martire, Sajina Dhungel, Elizabeth McCauley, Purbita Saha, Altair L Dube, Matthew S Gentry, Laura A Banaszynski, Ramon C Sun, Chintan K Kikani.

  Quiescent stem cells are activated in response to a mechanical or chemical injury to their tissue niche. Activated cells rapidly generate a heterogeneous progenitor population that regenerates the damaged tissues. While the transcriptional cadence that generates heterogeneity is known, the metabolic pathways influencing the transcriptional machinery to establish a heterogeneous progenitor population remains unclear. Here, we describe a novel pathway downstream of mitochondrial glutamine metabolism that confers stem cell heterogeneity and establishes differentiation competence by countering post-mitotic self-renewal machinery. We discovered that mitochondrial glutamine metabolism induces CBP/EP300-dependent acetylation of stem cell-specific kinase, PASK, resulting in its release from cytoplasmic granules and subsequent nuclear migration. In the nucleus, PASK catalytically outcompetes mitotic WDR5-anaphase-promoting complex/cyclosome (APC/C) interaction resulting in the loss of post-mitotic Pax7 expression and exit from self-renewal. In concordance with these findings, genetic or pharmacological inhibition of PASK or glutamine metabolism upregulated Pax7 expression, reduced stem cell heterogeneity, and blocked myogenesis in vitro and muscle regeneration in mice. These results explain a mechanism whereby stem cells co-opt the proliferative functions of glutamine metabolism to generate transcriptional heterogeneity and establish differentiation competence by countering the mitotic self-renewal network via nuclear PASK.

Keywords:  cell biology; human; mouse

DOI:  https://doi.org/10.7554/eLife.81717
Cancers (Basel). 2023 Apr 04. pii: 2144. [Epub ahead of print]15(7):

Lipid Metabolic Reprogramming in Embryonal Neoplasms with MYCN Amplification.

Jyotirmayee Talapatra, Mamatha M Reddy.

  Tumor cells reprogram their metabolism, including glucose, glutamine, nucleotide, lipid, and amino acids to meet their enhanced energy demands, redox balance, and requirement of biosynthetic substrates for uncontrolled cell proliferation. Altered lipid metabolism in cancer provides lipids for rapid membrane biogenesis, generates the energy required for unrestricted cell proliferation, and some of the lipids act as signaling pathway mediators. In this review, we focus on the role of lipid metabolism in embryonal neoplasms with MYCN dysregulation. We specifically review lipid metabolic reactions in neuroblastoma, retinoblastoma, medulloblastoma, Wilms tumor, and rhabdomyosarcoma and the possibility of targeting lipid metabolism. Additionally, the regulation of lipid metabolism by the MYCN oncogene is discussed.

Keywords:  MYCN; cancer; embryonal tumors; lipid metabolism; therapeutic targeting

DOI:  https://doi.org/10.3390/cancers15072144
Cancer Lett. 2023 Apr 11. pii: S0304-3835(23)00122-2. [Epub ahead of print] 216171

Single-cell RNA sequencing reveals XBP1-SLC38A2 axis as a metabolic regulator in cytotoxic T lymphocytes in multiple myeloma.

Yike Wan, Mengping Chen, Xin Li, Xiaofeng Han, Lu Zhong, Fei Xiao, Jia Liu, Jing Xiang, Jinxing Jiang, Xiaotong Chen, Junling Liu, Hua Li, Bin Li, Honghui Huang, Jian Hou.

  The mechanisms underlying the functional impairment and metabolic reprogramming of T lymphocytes in multiple myeloma (MM) have not been fully elucidated. In this study, single-cell RNA sequencing was used to compare gene expression profiles in T cells in bone marrow and peripheral blood of 10 newly diagnosed MM patients versus 3 healthy donors. Unbiased bioinformatics analysis revealed 9 cytotoxic T cell clusters. All 9 clusters in MM had higher expression of senescence markers (e.g., KLRG1 and CTSW) than the healthy control; some had higher expression of exhaustion-related markers (e.g., LAG3 and TNFRSF14). Pathway enrichment analyses showed downregulated amino acid metabolism and upregulated unfolded protein response (UPR) pathways, along with absent expression of glutamine transporter SLC38A2 and increased expression of UPR hallmark XBP1 in cytotoxic T cells in MM. In vitro studies revealed that XBP1 inhibited SLC38A2 by directly binding to its promoter, and silencing SLC38A2 resulted in decreased glutamine uptake and immune dysfunction of T cells. This study provided a landscape description of the immunosuppressive and metabolic features in T lymphocytes in MM, and suggested an important role of XBP1-SLC38A2 axis in T cell function.

Keywords:  Cell exhaustion; Cell senescence; Glutamine metabolism; Immune microenvironment; Unfolded protein response

DOI:  https://doi.org/10.1016/j.canlet.2023.216171
Front Nutr. 2023 ;10 1113228

Amino acids in hematologic malignancies: Current status and future perspective.

Mengyao Wang, Ailin Zhao, Meng Li, Ting Niu.

  In recent years, growing emphasis has been placed on amino acids and their role in hematologic malignancies. Cancer cell metabolism is altered during tumorigenesis and development to meet expanding energetic and biosynthetic demands. Amino acids not only act as energy-supplying substances, but also play a vital role via regulating key signaling pathways, modulating epigenetic factors and remodeling tumor microenvironment. Targeting amino acids may be an effective therapeutic approach to address the current therapeutic challenges. Here, we provide an updated overview of mechanisms by which amino acids facilitate tumor development and therapy resistance. We also summarize novel therapies targeting amino acids, focusing on recent advances in basic research and their potential clinical implications.

Keywords:  amino acid; glutaminolysis; glutathione; hematologic malignancy; metabolism; therapy

DOI:  https://doi.org/10.3389/fnut.2023.1113228
Cancer Cell. 2023 Apr 12. pii: S1535-6108(23)00087-9. [Epub ahead of print]

Phenotypic plasticity and reduced tissue retention of exhausted tumor-infiltrating T cells following neoadjuvant immunotherapy in head and neck cancer.

Cem Sievers, Marco Craveiro, Jay Friedman, Yvette Robbins, Xinping Yang, Ke Bai, Andy Nguyen, Jason M Redman, Raj Chari, Patrick Soon-Shiong, Jeffrey Schlom, James Gulley, Clint T Allen.

  Neoadjuvant immunotherapies (NITs) have led to clinical benefits in several cancers. Characterization of the molecular mechanisms underlying responses to NIT may lead to improved treatment strategies. Here we show that exhausted, tumor-infiltrating CD8+ T (Tex) cells display local and systemic responses to concurrent neoadjuvant TGF-β and PD-L1 blockade. NIT induces a significant and selective increase in circulating Tex cells associated with reduced intratumoral expression of the tissue-retention marker CD103. TGF-β-driven CD103 expression on CD8+ T cells is reversed following TGF-β neutralization in vitro, implicating TGF-β in T cell tissue retention and impaired systemic immunity. Transcriptional changes implicate T cell receptor signaling and glutamine metabolism as important determinants of enhanced or reduced Tex treatment response, respectively. Our analysis illustrates physiological and metabolic changes underlying T cell responses to NIT, highlighting the interplay between immunosuppression, tissue retention, and systemic anti-tumor immunity and suggest antagonism of T cell tissue retention as a promising neoadjuvant treatment strategy.

Keywords:  TGF-β; glutamine metabolism; neoadjuvant immunotherapy; neoepitope-specific T cells; single-cell transcriptomics; tissue-resident T cells

DOI:  https://doi.org/10.1016/j.ccell.2023.03.014
Front Endocrinol (Lausanne). 2023 ;14 1126271

Emerging role of substance and energy metabolism associated with neuroendocrine regulation in tumor cells.

Yingying Liu, Renjun Gu, Murong Gao, Yangwa Wei, Yu Shi, Xu Wang, Yihuang Gu, Xin Gu, Hongru Zhang.

  Cancer is the second most common cause of mortality in the world. One of the unresolved difficult pathological mechanism issues in malignant tumors is the imbalance of substance and energy metabolism of tumor cells. Cells maintain life through energy metabolism, and normal cells provide energy through mitochondrial oxidative phosphorylation to generate ATP, while tumor cells demonstrate different energy metabolism. Neuroendocrine control is crucial for tumor cells' consumption of nutrients and energy. As a result, better combinatorial therapeutic approaches will be made possible by knowing the neuroendocrine regulating mechanism of how the neuroendocrine system can fuel cellular metabolism. Here, the basics of metabolic remodeling in tumor cells for nutrients and metabolites are presented, showing how the neuroendocrine system regulates substance and energy metabolic pathways to satisfy tumor cell proliferation and survival requirements. In this context, targeting neuroendocrine regulatory pathways in tumor cell metabolism can beneficially enhance or temper tumor cell metabolism and serve as promising alternatives to available treatments.

Keywords:  energy; metabolism; neuroendocrine regulation; substance; tumor cells

DOI:  https://doi.org/10.3389/fendo.2023.1126271
Int Immunopharmacol. 2023 Apr 06. pii: S1567-5769(23)00471-X. [Epub ahead of print]118 110150

The combination of immunotherapy and a glutamine metabolism inhibitor represents an effective therapeutic strategy for advanced and metastatic murine pancreatic adenocarcinoma.

Andrea Frejlachova, Radka Lencova, Anna Venhauerova, Marketa Skalickova, Ondrej Uher, Veronika Caisova, Pavel Majer, Lukas Tenora, Per Hansen, Jindrich Chmelar, Jan Kopecky, Zhengping Zhuang, Karel Pacak, Jan Zenka.

  Despite constant advances in cancer research, the treatment of pancreatic adenocarcinoma remains extremely challenging. The intratumoral immunotherapy approach that was developed by our research group and was based on a combination of mannan-BAM, TLR ligands, and anti-CD40 antibody (MBTA) showed promising therapeutic effects in various murine tumor models, including a pancreatic adenocarcinoma model (Panc02). However, the efficacy of MBTA therapy in the Panc02 model was negatively correlated with tumor size at the time of therapy initiation. Here, we aimed to further improve the outcome of MBTA therapy in the Panc02 model using the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON). The combination of intratumoral MBTA therapy and intraperitoneal administration of DON resulted in the complete elimination of advanced Panc02 subcutaneous tumors (140.8 ± 46.8 mm3) in 50% of treated animals and was followed by development of long-term immune memory. In the bilateral Panc02 subcutaneous tumor model, we observed a significant reduction in tumor growth in both tumors as well as prolonged survival of treated animals. The appropriate timing and method of administration of DON were also addressed to maximize its therapeutic effects and minimize its side effects. In summary, our findings demonstrate that the intraperitoneal application of DON significantly improves the efficacy of intratumoral MBTA therapy in both advanced and bilateral Panc02 subcutaneous tumor murine models.

Keywords:  Cancer; Glutamine antagonist; Immunotherapy; Intratumoral; Pancreatic adenocarcinoma

DOI:  https://doi.org/10.1016/j.intimp.2023.110150
Cancers (Basel). 2023 Mar 23. pii: 1942. [Epub ahead of print]15(7):

The Interaction between Gut Microbiota and Host Amino Acids Metabolism in Multiple Myeloma.

Qin Yang, Yumou Wei, Yinghong Zhu, Jiaojiao Guo, Jingyu Zhang, Yanjuan He, Xin Li, Jing Liu, Wen Zhou.

  Although novel therapies have dramatically improved outcomes for multiple myeloma (MM) patients, relapse is inevitable and overall outcomes are heterogeneous. The gut microbiota is becoming increasingly recognized for its influence on host metabolism. To date, evidence has suggested that the gut microbiota contributes to MM, not only via the progressive activities of specific bacteria but also through the influence of the microbiota on host metabolism. Importantly, the abnormal amino acid metabolism, as well as the altered microbiome in MM, is becoming increasingly apparent, as is the influence on MM progression and the therapeutic response. Moreover, the gut-microbiota-host-amino-acid metabolism interaction in the progression of MM has been highlighted. Modulation of the gut microbiota (such as fecal microbiota transplantation, FMT) can be modified, representing a new angle in MM treatment that can improve outcomes. In this review, the relationship between gut microbiota, metabolism, and MM, together with strategies to modulate the microbiota, will be discussed, and some unanswered questions for ongoing and future research will be presented.

Keywords:  amino acid metabolism; gut microbiota; gut-microbiota–host-metabolic interaction; host metabolism; multiple myeloma

DOI:  https://doi.org/10.3390/cancers15071942