bims-glucam 2023-07-16 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2023–07–16
thirteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine metabolic microenvironment drives M2 macrophage polarization to mediate trastuzumab resistance in HER2-positive gastric cancer.
Metabolic reprogramming of cancer cells by JMJD6-mediated pre-mRNA splicing is associated with therapeutic response to splicing inhibitor.
Dietary Manipulation of Amino Acids for Cancer Therapy.
Mitochondria Deregulations in Cancer Offer Several Potential Targets of Therapeutic Interventions.
Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer.
Environmental cadmium exposure facilitates mammary tumorigenesis via reprogramming gut microbiota-mediated glutamine metabolism in MMTV-Erbb2 mice.
The stress sensor GCN2 differentially controls ribosome biogenesis in colon cancer according to the nutritional context.
Long Non-Coding RNAs and Metabolic Rewiring in Pancreatic Cancer.
Rewired Metabolism Caused by the Oncogenic Deregulation of MYC as an Attractive Therapeutic Target in Cancers.
Electron transport chain and mTOR inhibition synergistically decrease CD40 signaling and counteract venetoclax resistance in chronic lymphocytic leukemia.
Preoperative Glutamine Supplementation in Gastric Cancer-Thrombocyte Phagocytic Activity and Early Postoperative Outcomes.
Targeting Metabolic Vulnerabilities in Epstein-Barr Virus-Driven Proliferative Diseases.
αKG-driven RNA polymerase II transcription of cyclin D1 licenses malic enzyme 2 to promote cell-cycle progression.

Cancer Commun (Lond). 2023 Jul 11.

Glutamine metabolic microenvironment drives M2 macrophage polarization to mediate trastuzumab resistance in HER2-positive gastric cancer.

Xingbin Hu, Zhenfeng Ma, Beibei Xu, Shulong Li, Zhiqi Yao, Bishan Liang, Jiao Wang, Wangjun Liao, Li Lin, Chunling Wang, Siting Zheng, Qijing Wu, Qiong Huang, Le Yu, Fenghua Wang, Min Shi.

   BACKGROUND: Trastuzumab is a first-line targeted therapy for human epidermal growth factor receptor-2 (HER2)-positive gastric cancer. However, the inevitable occurrence of acquired trastuzumab resistance limits the drug benefit, and there is currently no effective reversal measure. Existing researches on the mechanism of trastuzumab resistance mainly focused on tumor cells themselves, while the understanding of the mechanisms of environment-mediated drug resistance is relatively lacking. This study aimed to further explore the mechanisms of trastuzumab resistance to identify strategies to promote survival in these patients.
METHODS: Trastuzumab-sensitive and trastuzumab-resistant HER2-positive tumor tissues and cells were collected for transcriptome sequencing. Bioinformatics were used to analyze cell subtypes, metabolic pathways, and molecular signaling pathways. Changes in microenvironmental indicators (such as macrophage, angiogenesis, and metabolism) were verified by immunofluorescence (IF) and immunohistochemical (IHC) analyses. Finally, a multi-scale agent-based model (ABM) was constructed. The effects of combination treatment were further validated in nude mice to verify these effects predicted by the ABM.
RESULTS: Based on transcriptome sequencing, molecular biology, and in vivo experiments, we found that the level of glutamine metabolism in trastuzumab-resistant HER2-positive cells was increased, and glutaminase 1 (GLS1) was significantly overexpressed. Meanwhile, tumor-derived GLS1 microvesicles drove M2 macrophage polarization. Furthermore, angiogenesis promoted trastuzumab resistance. IHC showed high glutamine metabolism, M2 macrophage polarization, and angiogenesis in trastuzumab-resistant HER2-positive tumor tissues from patients and nude mice. Mechanistically, the cell division cycle 42 (CDC42) promoted GLS1 expression in tumor cells by activating nuclear factor kappa-B (NF-κB) p65 and drove GLS1 microvesicle secretion through IQ motif-containing GTPase-activating protein 1 (IQGAP1). Based on the ABM and in vivo experiments, we confirmed that the combination of anti-glutamine metabolism, anti-angiogenesis, and pro-M1 polarization therapy had the best effect in reversing trastuzumab resistance in HER2-positive gastric cancer.
CONCLUSIONS: This study revealed that tumor cells secrete GLS1 microvesicles via CDC42 to promote glutamine metabolism, M2 macrophage polarization, and pro-angiogenic function of macrophages, leading to acquired trastuzumab resistance in HER2-positive gastric cancer. A combination of anti-glutamine metabolism, anti-angiogenesis, and pro-M1 polarization therapy may provide a new insight into reversing trastuzumab resistance.

Keywords:  Gastric cancer; glutamine metabolism; macrophage; mathematical model; microvesicles; trastuzumab

DOI:  https://doi.org/10.1002/cac2.12459
bioRxiv. 2023 Jun 28. pii: 2023.06.26.546606. [Epub ahead of print]

Metabolic reprogramming of cancer cells by JMJD6-mediated pre-mRNA splicing is associated with therapeutic response to splicing inhibitor.

Carolyn Jablonowski, Waise Quarni, Shivendra Singh, Haiyan Tan, Dhanushka Hewa Bostanthirige, Hongjian Jin, Jie Fang, Ti-Cheng Chang, David Finkelstein, Ji-Hoon Cho, Dongli Hu, Vishwajeeth Pagala, Sadie Miki Sakurada, Shondra M Pruett-Miller, Ruoning Wang, Andrew Murphy, Kevin Freeman, Junmin Peng, Andrew M Davidoff, Gang Wu, Jun Yang.

Dysregulated pre-mRNA splicing and metabolism are two hallmarks of MYC-driven cancers. Pharmacological inhibition of both processes has been extensively investigated as potential therapeutic avenues in preclinical and clinical studies. However, how pre-mRNA splicing and metabolism are orchestrated in response to oncogenic stress and therapies is poorly understood. Here, we demonstrate that JMJD6 acts as a hub connecting splicing and metabolism in MYC-driven neuroblastoma. JMJD6 cooperates with MYC in cellular transformation by physically interacting with RNA binding proteins involved in pre-mRNA splicing and protein homeostasis. Notably, JMJD6 controls the alternative splicing of two isoforms of glutaminase (GLS), namely kidney-type glutaminase (KGA) and glutaminase C (GAC), which are rate-limiting enzymes of glutaminolysis in the central carbon metabolism in neuroblastoma. Further, we show that JMJD6 is correlated with the anti-cancer activity of indisulam, a "molecular glue" that degrades splicing factor RBM39, which complexes with JMJD6. The indisulam-mediated cancer cell killing is at least partly dependent on the glutamine-related metabolic pathway mediated by JMJD6. Our findings reveal a cancer-promoting metabolic program is coupled with alternative pre-mRNA splicing through JMJD6, providing a rationale to target JMJD6 as a therapeutic avenue for treating MYC-driven cancers.

DOI: https://doi.org/10.1101/2023.06.26.546606
Nutrients. 2023 Jun 25. pii: 2879. [Epub ahead of print]15(13):

Dietary Manipulation of Amino Acids for Cancer Therapy.

Julio José Jiménez-Alonso, Miguel López-Lázaro.

  Cancer cells cannot proliferate and survive unless they obtain sufficient levels of the 20 proteinogenic amino acids (AAs). Unlike normal cells, cancer cells have genetic and metabolic alterations that may limit their capacity to obtain adequate levels of the 20 AAs in challenging metabolic environments. However, since normal diets provide all AAs at relatively constant levels and ratios, these potentially lethal genetic and metabolic defects are eventually harmless to cancer cells. If we temporarily replace the normal diet of cancer patients with artificial diets in which the levels of specific AAs are manipulated, cancer cells may be unable to proliferate and survive. This article reviews in vivo studies that have evaluated the antitumor activity of diets restricted in or supplemented with the 20 proteinogenic AAs, individually and in combination. It also reviews our recent studies that show that manipulating the levels of several AAs simultaneously can lead to marked survival improvements in mice with metastatic cancers.

Keywords:  anticancer activity; arginine; artificial diets; asparagine; cancer metabolism; cysteine; essential amino acids; glutamine; in vivo; leucine; methionine; mice; non-essential amino acids; restriction; serine

DOI:  https://doi.org/10.3390/nu15132879
Int J Mol Sci. 2023 Jun 21. pii: 10420. [Epub ahead of print]24(13):

Mitochondria Deregulations in Cancer Offer Several Potential Targets of Therapeutic Interventions.

Clara Musicco, Anna Signorile, Vito Pesce, Paola Loguercio Polosa, Antonella Cormio.

  Mitochondria play a key role in cancer and their involvement is not limited to the production of ATP only. Mitochondria also produce reactive oxygen species and building blocks to sustain rapid cell proliferation; thus, the deregulation of mitochondrial function is associated with cancer disease development and progression. In cancer cells, a metabolic reprogramming takes place through a different modulation of the mitochondrial metabolic pathways, including oxidative phosphorylation, fatty acid oxidation, the Krebs cycle, glutamine and heme metabolism. Alterations of mitochondrial homeostasis, in particular, of mitochondrial biogenesis, mitophagy, dynamics, redox balance, and protein homeostasis, were also observed in cancer cells. The use of drugs acting on mitochondrial destabilization may represent a promising therapeutic approach in tumors in which mitochondrial respiration is the predominant energy source. In this review, we summarize the main mitochondrial features and metabolic pathways altered in cancer cells, moreover, we present the best known drugs that, by acting on mitochondrial homeostasis and metabolic pathways, may induce mitochondrial alterations and cancer cell death. In addition, new strategies that induce mitochondrial damage, such as photodynamic, photothermal and chemodynamic therapies, and the development of nanoformulations that specifically target drugs in mitochondria are also described. Thus, mitochondria-targeted drugs may open new frontiers to a tailored and personalized cancer therapy.

Keywords:  ROS; cancer therapy; mitochondrial drug delivery; mitochondrial inhibitors; targeting mitochondria

DOI:  https://doi.org/10.3390/ijms241310420
bioRxiv. 2023 Jun 28. pii: 2023.06.27.546750. [Epub ahead of print]

Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer.

Ray Pillai, Sarah E LeBoeuf, Yuan Hao, Connie New, Jenna L E Blum, Ali Rashidfarrokhi, Shih Ming Huang, Christian Bahamon, Warren L Wu, Burcu Karadal-Ferrena, Alberto Herrera, Ellie Ivanova, Michael Cross, Jozef P Bossowski, Hongyu Ding, Makiko Hayashi, Sahith Rajalingam, Triantafyllia Karakousi, Volkan I Sayin, Kamal M Khanna, Kwok-Kin Wong, Robert Wild, Aristotelis Tsirigos, John T Poirier, Charles M Rudin, Shawn M Davidson, Sergei B Koralov, Thales Papagiannakopoulos.

Loss-of-function mutations in KEAP1 frequently occur in lung cancer and are associated with resistance to standard of care treatment, highlighting the need for the development of targeted therapies. We have previously shown that KEAP1 mutant tumors have increased glutamine consumption to support the metabolic rewiring associated with NRF2 activation. Here, using patient-derived xenograft models and antigenic orthotopic lung cancer models, we show that the novel glutamine antagonist DRP-104 impairs the growth of KEAP1 mutant tumors. We find that DRP-104 suppresses KEAP1 mutant tumor growth by inhibiting glutamine-dependent nucleotide synthesis and promoting anti-tumor CD4 and CD8 T cell responses. Using multimodal single-cell sequencing and ex vivo functional assays, we discover that DRP-104 reverses T cell exhaustion and enhances the function of CD4 and CD8 T cells culminating in an improved response to anti-PD1 therapy. Our pre-clinical findings provide compelling evidence that DRP-104, currently in phase 1 clinical trials, offers a promising therapeutic approach for treating patients with KEAP1 mutant lung cancer. Furthermore, we demonstrate that by combining DRP-104 with checkpoint inhibition, we can achieve suppression of tumor intrinsic metabolism and augmentation of anti-tumor T cell responses.

DOI: https://doi.org/10.1101/2023.06.27.546750
Sci Total Environ. 2023 Jul 08. pii: S0048-9697(23)03971-2. [Epub ahead of print] 165348

Environmental cadmium exposure facilitates mammary tumorigenesis via reprogramming gut microbiota-mediated glutamine metabolism in MMTV-Erbb2 mice.

Yang Yue, Huadong Zhang, Ping Deng, Miduo Tan, Chengzhi Chen, Bo Tang, Jingdian Li, Fengqiong Chen, Qi Zhao, Ling Li, Rongrong Hao, Hui Wang, Yan Luo, Li Tian, Jia Xie, Mengyan Chen, Zhengping Yu, Zhou Zhou, Huifeng Pi.

  Cadmium (Cd) is a heavy metal that has been widely reported to be linked to the onset and progression of breast cancer (BC). However, the mechanism of Cd-induced mammary tumorigenesis remains elusive. In our study, a transgenic mouse model that spontaneously develops tumors through overexpression of wild-type Erbb2 (MMTV-Erbb2) was constructed to investigate the effects of Cd exposure on BC tumorigenesis. The results showed that oral exposure to 3.6 mg/L Cd for 23 weeks dramatically accelerated tumor appearance and growth, increased Ki67 density and enhanced focal necrosis and neovascularization in the tumor tissue of MMTV-Erbb2 mice. Notably, Cd exposure enhanced glutamine (Gln) metabolism in tumor tissue, and 6-diazo-5-oxo-l-norleucine (DON), a Gln metabolism antagonist, inhibited Cd-induced breast carcinogenesis. Then our metagenomic sequencing and mass spectrometry-based metabolomics confirmed that Cd exposure disturbed gut microbiota homeostasis, especially Helicobacter and Campylobacter abundance remodeling, which altered the gut metabolic homeostasis of Gln. Moreover, intratumoral Gln metabolism profoundly increased under Cd-elevated gut permeability. Importantly, depletion of microbiota with an antibiotic cocktail (AbX) treatment led to a significant delay in the appearance of palpable tumors, inhibition of tumor growth, decrease in tumor weight, reduction in Ki67 expression and low-grade pathology in Cd-exposed MMTV-Erbb2 mice. Also, transplantation of Cd-modulated microbiota decreased tumor latency, accelerated tumor growth, increased tumor weight, upregulated Ki67 expression and exacerbated neovascularization as well as focal necrosis in MMTV-Erbb2 mice. In summary, Cd exposure induced gut microbiota dysbiosis, elevated gut permeability and increased intratumoral Gln metabolism, leading to the promotion of mammary tumorigenesis. This study provides novel insights into environmental Cd exposure-mediated carcinogenesis.

Keywords:  Breast cancer; Cadmium; Glutamine metabolism; Gut dysbiosis; MMTV-Erbb2 mice

DOI:  https://doi.org/10.1016/j.scitotenv.2023.165348
Mol Oncol. 2023 Jul 15.

The stress sensor GCN2 differentially controls ribosome biogenesis in colon cancer according to the nutritional context.

Marie Piecyk, Mouna Triki, Pierre-Alexandre Laval, Cedric Duret, Joelle Fauvre, Laura Cussonneau, Christelle Machon, Jerôme Guitton, Nicolas Rama, Benjamin Gibert, Gabriel Ichim, Frederic Catez, Fleur Bourdelais, Sebastien Durand, Jean-Jacques Diaz, Isabelle Coste, Toufic Renno, Serge N Manié, Nicolas Aznar, Stephane Ansieau, Carole Ferraro-Peyret, Cedric Chaveroux.

  Nutrient availability is a key determinant of tumor cell behavior. While nutrient-rich conditions favor proliferation and tumor growth, scarcity, and particularly glutamine starvation, promotes cell dedifferentiation and chemoresistance. Here, linking ribosome biogenesis plasticity with tumor cell fate, we uncover that the amino acid sensor general control non-derepressible 2 (GCN2; also known as eIF-2-alpha kinase 4) represses the expression of the precursor of ribosomal RNA (rRNA), 47S, under metabolic stress. We show that blockade of GCN2 triggers cell death by an irremediable nucleolar stress and subsequent TP53-mediated apoptosis in patient-derived models of colon adenocarcinoma (COAD). In nutrient-rich conditions, a cell-autonomous GCN2 activity supports cell proliferation by stimulating 47S rRNA transcription, independently of the canonical integrated stress response (ISR) axis. Impairment of GCN2 activity prevents nuclear translocation of methionyl-tRNA synthetase (MetRS), resulting in nucleolar stress, mTORC1 inhibition and, ultimately, autophagy induction. Inhibition of the GCN2-MetRS axis drastically improves the cytotoxicity of RNA polymerase I (RNA pol I) inhibitors, including the first-line chemotherapy oxaliplatin, on patient-derived COAD tumoroids. Our data thus reveal that GCN2 differentially controls ribosome biogenesis according to the nutritional context. Furthermore, pharmacological co-inhibition of the two GCN2 branches and RNA pol I activity may represent a valuable strategy for elimination of proliferative and metabolically-stressed COAD cells.

Keywords:  Colon cancer; GCN2; Methionyl-tRNA synthetase; Nucleolar stress; Ribosome biogenesis

DOI:  https://doi.org/10.1002/1878-0261.13491
Cancers (Basel). 2023 Jul 04. pii: 3486. [Epub ahead of print]15(13):

Long Non-Coding RNAs and Metabolic Rewiring in Pancreatic Cancer.

Bruna Dalmasso, Paola Ghiorzo.

  Pancreatic adenocarcinoma is a highly aggressive disease with a poor prognosis. The reprogramming of energetic metabolism has long been implicated in pancreatic tumorigenesis and/or resistance to treatment. Considering that long non-coding RNA dysregulation has been described both in cancerogenesis and in the altered homeostasis of several metabolic pathways, metabolism-associated lncRNAs can contribute to pancreatic cancer evolution. The objective of this review is to assess the burden of lncRNA dysregulation in pancreatic cancer metabolic reprogramming, and its effect on this tumor's natural course and response to treatment. Therefore, we reviewed the available literature to assess whether metabolism-associated lncRNAs have been found to be differentially expressed in pancreatic cancer, as well as whether experimental evidence of their role in such pathways can be demonstrated. Specifically, we provide a comprehensive overview of lncRNAs that are implicated in hypoxia-related pathways, as well as in the reprogramming of autophagy, lipid metabolism, and amino acid metabolism. Our review gathers background material for further research on possible applications of metabolism-associated lncRNAs as diagnostic/prognostic biomarkers and/or as potential therapeutic targets in pancreatic adenocarcinoma.

Keywords:  PDAC; autophagy; chemoresistance; hypoxia; long non-coding RNA; metabolic rewiring; pancreatic cancer; therapeutic targets

DOI:  https://doi.org/10.3390/cancers15133486
Cells. 2023 Jun 29. pii: 1745. [Epub ahead of print]12(13):

Rewired Metabolism Caused by the Oncogenic Deregulation of MYC as an Attractive Therapeutic Target in Cancers.

Laura Vízkeleti, Sándor Spisák.

  MYC is one of the most deregulated oncogenes on multiple levels in cancer. As a node transcription factor, MYC plays a diverse regulatory role in many cellular processes, including cell cycle and metabolism, both in physiological and pathological conditions. The relentless growth and proliferation of tumor cells lead to an insatiable demand for energy and nutrients, which requires the rewiring of cellular metabolism. As MYC can orchestrate all aspects of cellular metabolism, its altered regulation plays a central role in these processes, such as the Warburg effect, and is a well-established hallmark of cancer development. However, our current knowledge of MYC suggests that its spatial- and concentration-dependent contribution to tumorigenesis depends more on changes in the global or relative expression of target genes. As the direct targeting of MYC is proven to be challenging due to its relatively high toxicity, understanding its underlying regulatory mechanisms is essential for the development of tumor-selective targeted therapies. The aim of this review is to comprehensively summarize the diverse forms of MYC oncogenic deregulation, including DNA-, transcriptional- and post-translational level alterations, and their consequences for cellular metabolism. Furthermore, we also review the currently available and potentially attractive therapeutic options that exploit the vulnerability arising from the metabolic rearrangement of MYC-driven tumors.

Keywords:  MYC deregulation; altered cellular metabolism; protooncogene; therapeutic targets

DOI:  https://doi.org/10.3390/cells12131745
Haematologica. 2023 Jul 13.

Electron transport chain and mTOR inhibition synergistically decrease CD40 signaling and counteract venetoclax resistance in chronic lymphocytic leukemia.

Zhenghao Chen, Gaspard Cretenet, Valeria Carnazzo, Helga Simon-Molas, Arnon P Kater, Gerritje J W van der Windt, Eric Eldering.

CD40 signaling upregulates BCL-XL and MCL-1 expression in the chronic lymphocytic leukemia (CLL) lymph node microenvironment (TME), affording resistance to the BCL-2 inhibitor venetoclax (VEN). VEN resistance in the therapeutic setting and after long-term laboratory selection has been linked to metabolic alterations, but the underlying mechanism(s) are unknown. We aimed here to discover how CD40 stimulation as a model for TME-mediated metabolic changes, affects VEN sensitivity/resistance. CD40 stimulation increased oxidative phosphorylation (OXPHOS) and glycolysis, but only OXPHOS inhibition countered VEN resistance. Furthermore, blocking mitochondrial import of pyruvate, glutamine or fatty acids affected CLL metabolism, but did not prevent CD40-mediated VEN resistance. In contrast, inhibition of the electron transport chain (ETC) at complex I, III and V attenuated CLL activation and ATP production, and downregulated MCL-1 and BCL-XL, correlating with reduced CD40 surface expression. Moreover, ETC inhibition equaled mTOR1/2 but not mTOR1 inhibition alone for VEN resistance, and all three pathways were linked to control of general protein translation. In line with this, ETC plus mTOR inhibition synergistically counteracted VEN resistance. These findings link oxidative CLL metabolism to CD40 expression and cellular signaling, and may hold clinical potential.

DOI: https://doi.org/10.3324/haematol.2023.282760
Nutrients. 2023 Jun 27. pii: 2911. [Epub ahead of print]15(13):

Preoperative Glutamine Supplementation in Gastric Cancer-Thrombocyte Phagocytic Activity and Early Postoperative Outcomes.

Zbigniew Kamocki, Joanna Matowicka-Karna, Anna Jurczuk, Anna Milewska, Amanda Niewinski, Konrad Zareba, Boguslaw Kedra.

   BACKGROUND: The aim of this study was to determine the phagocytic activity of thrombocytes in patients with gastric cancer and to assess the effect of oral and parenteral preoperative glutamine-based immunonutrition on nutritional status, thrombocyte phagocytic activity, and early postoperative outcomes.
METHODS: Patients suffering from invasive gastric cancer had been treated with preoperative immunonutrition with glutamine, and they were compared to patients without nutritional treatment. Nutritional status, percentage of weight loss, and BMI were assessed. Levels of total protein, albumin, cholesterol, triglycerides, platelets, and their phagocytic ability were measured twice. Postsurgical complications were assessed via the Clavien-Dindo classification.
RESULTS: Group I consisted of 20 patients with an oral glutamine-10 g daily. Group II had 38 patients who received intravenous glutamine, 1.5 mL per kg body weight of Dipeptiven. Group III consisted of 25 patients who did not receive preoperative immunonutrition. In total, 47% of patients in Group I, 54% of patients in Group II, and 33% of patients in Group III were malnourished. In Group I, the percentage of phagocytizing platelet (%PhP) was 1.1 preoperatively and 1.2 postoperatively. The phagocytic index (PhI) was 1.0 and 1.1. In Group II, %PhP was 1.1 and 1.2 and PhI was 1.0 and 1.1. In Group III, the %PhP was 1.0 and 1.2 and PhI was 1.0 and 1.1. An increase in triglyceride level was observed in both immunonutrition groups. There was a decline in total protein and albumin level in Group II. In Group III, there was a decline in total protein, albumin, and cholesterol level. The total platelet count and PhI were increased in both immunonutrition groups. There was also a rise in %PhP in Group II. In Group III, there was a rise in blood platelet level, %PhP, and PhI. The complication rates were 53% in Group I, 29% in Group II, and 40% in Group III.
CONCLUSIONS: In invasive gastric cancer, laboratory nutritional parameters are significantly reduced, causing malnutrition in 44.7% of patients. Oral glutamine supplementation inhibited the postoperative decline in protein metabolism parameters; however, this did not affect the reduction in the percentage of postoperative complications. Glutamine used preoperatively significantly reduced the percentage of serious surgical complications, regardless of the way it was supplemented. Patients with invasive gastric cancer have a significant decrease in platelet phagocytic activity. The administered preoperative parenteral nutrition and the surgical procedure itself influenced the improvement of the phagocytic activity of blood platelets. Glutamine did not have this effect, regardless of the route of administration.

Keywords:  blood platelet phagocytosis; gastric cancer; glutamine; nutritional status; postoperative complications

DOI:  https://doi.org/10.3390/nu15132911
Cancers (Basel). 2023 Jun 29. pii: 3412. [Epub ahead of print]15(13):

Targeting Metabolic Vulnerabilities in Epstein-Barr Virus-Driven Proliferative Diseases.

Nicole Yong Ting Leung, Liang Wei Wang.

  The metabolism of cancer cells and Epstein-Barr virus (EBV) infected cells have remarkable similarities. Cancer cells frequently reprogram metabolic pathways to augment their ability to support abnormal rates of proliferation and promote intra-organismal spread through metastatic invasion. On the other hand, EBV is also capable of manipulating host cell metabolism to enable sustained growth and division during latency as well as intra- and inter-individual transmission during lytic replication. It comes as no surprise that EBV, the first oncogenic virus to be described in humans, is a key driver for a significant fraction of human malignancies in the world (~1% of all cancers), both in terms of new diagnoses and attributable deaths each year. Understanding the contributions of metabolic pathways that underpin transformation and virus replication will be important for delineating new therapeutic targets and designing nutritional interventions to reduce disease burden. In this review, we summarise research hitherto conducted on the means and impact of various metabolic changes induced by EBV and discuss existing and potential treatment options targeting metabolic vulnerabilities in EBV-associated diseases.

Keywords:  EBV; Epstein–Barr virus; cancer biology; cancer metabolism; latency; lytic infection; oncometabolic pathways

DOI:  https://doi.org/10.3390/cancers15133412
Cell Rep. 2023 Jul 07. pii: S2211-1247(23)00781-7. [Epub ahead of print]42(7): 112770

αKG-driven RNA polymerase II transcription of cyclin D1 licenses malic enzyme 2 to promote cell-cycle progression.

Yanting Yang, Zhenxi Zhang, Wei Li, Yufan Si, Li Li, Wenjing Du.

  Increased metabolic activity usually provides energy and nutrients for biomass synthesis and is indispensable for the progression of the cell cycle. Here, we find a role for α-ketoglutarate (αKG) generation in regulating cell-cycle gene transcription. A reduction in cellular αKG levels triggered by malic enzyme 2 (ME2) or isocitrate dehydrogenase 1 (IDH1) depletion leads to a pronounced arrest in G1 phase, while αKG supplementation promotes cell-cycle progression. Mechanistically, αKG directly binds to RNA polymerase II (RNAPII) and increases the level of RNAPII binding to the cyclin D1 gene promoter via promoting pre-initiation complex (PIC) assembly, consequently enhancing cyclin D1 transcription. Notably, αKG addition is sufficient to restore cyclin D1 expression in ME2- or IDH1-depleted cells, facilitating cell-cycle progression and proliferation in these cells. Therefore, our findings indicate a function of αKG in gene transcriptional regulation and cell-cycle control.

Keywords:  CP: Molecular biology; RNA polymerase II; cell cycle; cyclin D1; malic enzyme 2; α-ketoglutarate

DOI:  https://doi.org/10.1016/j.celrep.2023.112770