bims-glucam 2024-02-04 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024‒02‒04
fifteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Does oncolytic viruses-mediated metabolic reprogramming benefit or harm the immune microenvironment?
Cancer metabolism and carcinogenesis.
Cell polarity proteins promote macropinocytosis in response to metabolic stress.
The glutaminase inhibitor CB-839 targets metabolic dependencies of JAK2-mutant hematopoiesis in MPN.
Glutamine analogs for pancreatic cancer therapy.
Copper drives remodeling of metabolic state and progression of clear cell renal cell carcinoma.
Farnesoid X receptor agonist tropifexor detoxifies ammonia by regulating the glutamine metabolism and urea cycles in cholestatic livers.
Enhancement of de novo lipogenesis by the IDH1 and IDH2-dependent reverse TCA cycle maintains the growth and angiogenic capacity of bone marrow-derived endothelial progenitor cells under hypoxia.
Metabolic reprogramming in the tumor microenvironment of liver cancer.
A novel diabetic foot ulcer diagnostic model: identification and analysis of genes related to glutamine metabolism and immune infiltration.
Should the standard model of cellular energy metabolism be reconsidered? Possible coupling between the pentose phosphate pathway, glycolysis and extra-mitochondrial oxidative phosphorylation.
Distinct specificities of the HEMK2 protein methyltransferase in methylation of glutamine and lysine residues.
The unfolded protein response-glutathione metabolism axis: A novel target of a cycloruthenated complexes bypassing tumor resistance mechanisms.
Oncometabolite 2-hydroxyglutarate regulates anti-tumor immunity.
Nanosensors Monitor Intracellular GSH Depletion: GSH Triggers Cu(II) for Tumor Imaging and Inhibition.

FASEB J. 2024 Feb 15. 38(3): e23450

Does oncolytic viruses-mediated metabolic reprogramming benefit or harm the immune microenvironment?

Chengcheng Peng, Pengpeng Xiao, Nan Li.

  Oncolytic virus immunotherapy as a new tumor therapy has made remarkable achievements in clinical practice. And metabolic reprogramming mediated by oncolytic virus has a significant impact on the immune microenvironment. This review summarized the reprogramming of host cell glucose metabolism, lipid metabolism, oxidative phosphorylation, and glutamine metabolism by oncolytic virus and illustrated the effects of metabolic reprogramming on the immune microenvironment. It was found that oncolytic virus-induced reprogramming of glucose metabolism in tumor cells has both beneficial and detrimental effects on the immune microenvironment. In addition, oncolytic virus can promote fatty acid synthesis in tumor cells, inhibit oxidative phosphorylation, and promote glutamine catabolism, which facilitates the anti-tumor immune function of immune cells. Therefore, targeted metabolic reprogramming is a new direction to improve the efficacy of oncolytic virus immunotherapy.

Keywords:  glucose metabolism; glutamine metabolism; immune microenvironment; lipid metabolism; metabolic reprogramming; oncolytic virus; oxidative phosphorylation

DOI:  https://doi.org/10.1096/fj.202301947RR
Exp Hematol Oncol. 2024 Jan 29. 13(1): 10

Cancer metabolism and carcinogenesis.

Jianqiang Yang, Chloe Shay, Nabil F Saba, Yong Teng.

  Metabolic reprogramming is an emerging hallmark of cancer cells, enabling them to meet increased nutrient and energy demands while withstanding the challenging microenvironment. Cancer cells can switch their metabolic pathways, allowing them to adapt to different microenvironments and therapeutic interventions. This refers to metabolic heterogeneity, in which different cell populations use different metabolic pathways to sustain their survival and proliferation and impact their response to conventional cancer therapies. Thus, targeting cancer metabolic heterogeneity represents an innovative therapeutic avenue with the potential to overcome treatment resistance and improve therapeutic outcomes. This review discusses the metabolic patterns of different cancer cell populations and developmental stages, summarizes the molecular mechanisms involved in the intricate interactions within cancer metabolism, and highlights the clinical potential of targeting metabolic vulnerabilities as a promising therapeutic regimen. We aim to unravel the complex of metabolic characteristics and develop personalized treatment approaches to address distinct metabolic traits, ultimately enhancing patient outcomes.

Keywords:  Heterogeneous treatment effect; Metabolic exchange and integration; Metabolic heterogeneity; Metabolic patterns and regulation; Tumor heterogeneity

DOI:  https://doi.org/10.1186/s40164-024-00482-x
bioRxiv. 2024 Jan 30. pii: 2024.01.16.575943. [Epub ahead of print]

Cell polarity proteins promote macropinocytosis in response to metabolic stress.

Guillem Lambies, Szu-Wei Lee, Karen Duong-Polk, Pedro Aza-Blanc, Swetha Maganti, David W Dawson, Cosimo Commisso.

Macropinocytosis has emerged as a nutrient-scavenging pathway that cancer cells exploit to survive the nutrient-deprived conditions of the tumor microenvironment. Cancer cells are especially reliant on glutamine for their survival, and in pancreatic ductal adenocarcinoma (PDAC) cells, glutamine deficiency can enhance the stimulation of macropinocytosis, allowing the cells to escape metabolic stress through the production of extracellular-protein-derived amino acids. Here, we identify the atypical protein kinase C (aPKC) enzymes, PKCζ and PKCι as novel regulators of macropinocytosis. In normal epithelial cells, aPKCs are known to regulate cell polarity in association with the scaffold proteins Par3 and Par6, controlling the function of several targets, including the Par1 kinases. In PDAC cells, we identify that each of these cell polarity proteins are required for glutamine stress-induced macropinocytosis. Mechanistically, we find that the aPKCs are regulated by EGFR signaling or by the transcription factor CREM to promote the relocation of Par3 to microtubules, facilitating macropinocytosis in a dynein-dependent manner. Importantly, we determine that cell fitness impairment caused by aPKC depletion is rescued by the restoration of macropinocytosis and that aPKCs support PDAC growth in vivo. These results identify a previously unappreciated role for cell polarity proteins in the regulation of macropinocytosis and provide a better understanding of the mechanistic underpinnings that control macropinocytic uptake in the context of metabolic stress.

DOI: https://doi.org/10.1101/2024.01.16.575943
Blood Adv. 2024 Jan 31. pii: bloodadvances.2023010950. [Epub ahead of print]

The glutaminase inhibitor CB-839 targets metabolic dependencies of JAK2-mutant hematopoiesis in MPN.

Marc Usart, Nils Hansen, Jan Stetka, Tiago Almeida Fonseca, Alexandre Guy, Quentin Kimmerlin, Shivam Rai, Hui Hao-Shen, Julien Roux, Stefan Dirnhofer, Radek C Skoda.

Hyperproliferation of myeloid and erythroid cells in myeloproliferative neoplasms driven by the JAK2-V617F mutation is associated with altered metabolism. Given the central role of glutamine in anabolic and catabolic pathways, we examined the effects of pharmacologically inhibiting glutaminolysis, i.e. the conversion of glutamine (Gln) to glutamate (Glu), using CB-839, a small molecular inhibitor of the enzyme glutaminase (GLS). We show that CB-839 strongly reduced the mitochondrial respiration rate of bone marrow cells from JAK2-V617F mutant (VF) mice, demonstrating a marked dependence of these cells on Gln-derived ATP production. Consistently, in vivo treatment with CB-839 normalized blood glucose levels, reduced splenomegaly and decreased erythrocytosis in VF mice. These effects were more pronounced when CB-839 was combined with the JAK1/2 inhibitor ruxolitinib or the glycolysis inhibitor 3PO, indicating possible synergies when co-targeting different metabolic and oncogenic pathways. Furthermore, we show that the inhibition of glutaminolysis with CB-839 preferentially lowered the proportion of JAK2-mutant hematopoietic stem cells (HSCs). The total number of HSCs was decreased by CB-839, primarily by reducing HSCs in the G1 phase of the cell cycle. CB-839 in combination with ruxolitinib also strongly reduced myelofibrosis at later stages of MPN. In line with the effects shown in mice, proliferation of CD34+ hematopoietic stem and progenitor cells from PV patients was inhibited by CB-839 at nanomolar concentrations. These data suggest that inhibiting glutaminase alone or in combination with inhibitors of glycolysis or JAK2 inhibitors represents an attractive new therapeutic approach to MPN.

DOI: https://doi.org/10.1182/bloodadvances.2023010950
Nat Cancer. 2024 Jan;5(1): 2-4

Glutamine analogs for pancreatic cancer therapy.

Nada Y Kalaany.

DOI: https://doi.org/10.1038/s43018-023-00678-w
bioRxiv. 2024 Jan 19. pii: 2024.01.16.575895. [Epub ahead of print]

Copper drives remodeling of metabolic state and progression of clear cell renal cell carcinoma.

Megan E Bischoff, Behrouz Shamsaei, Juechen Yang, Dina Secic, Bhargav Vemuri, Julie A Reisz, Angelo D'Alessandro, Caterina Bartolacci, Rafal Adamczak, Lucas Schmidt, Jiang Wang, Amelia Martines, Jacek Biesiada, Katherine E Vest, Pier P Scaglioni, David R Plas, Krushna C Patra, Shuchi Gulati, Julio A Landero Figueroa, Jarek Meller, J Tom Cunningham, Maria F Czyzyk-Krzeska.

Copper (Cu) is an essential trace element required for mitochondrial respiration. Late-stage clear cell renal cell carcinoma (ccRCC) accumulates Cu and allocates it to mitochondrial cytochrome c oxidase. We show that Cu drives coordinated metabolic remodeling of bioenergy, biosynthesis and redox homeostasis, promoting tumor growth and progression of ccRCC. Specifically, Cu induces TCA cycle-dependent oxidation of glucose and its utilization for glutathione biosynthesis to protect against H 2 O 2 generated during mitochondrial respiration, therefore coordinating bioenergy production with redox protection. scRNA-seq determined that ccRCC progression involves increased expression of subunits of respiratory complexes, genes in glutathione and Cu metabolism, and NRF2 targets, alongside a decrease in HIF activity, a hallmark of ccRCC. Spatial transcriptomics identified that proliferating cancer cells are embedded in clusters of cells with oxidative metabolism supporting effects of metabolic states on ccRCC progression. Our work establishes novel vulnerabilities with potential for therapeutic interventions in ccRCC. Accumulation of copper is associated with progression and relapse of ccRCC and drives tumor growth.Cu accumulation and allocation to cytochrome c oxidase (CuCOX) remodels metabolism coupling energy production and nucleotide biosynthesis with maintenance of redox homeostasis.Cu induces oxidative phosphorylation via alterations in the mitochondrial proteome and lipidome necessary for the formation of the respiratory supercomplexes. Cu stimulates glutathione biosynthesis and glutathione derived specifically from glucose is necessary for survival of Cu Hi cells. Biosynthesis of glucose-derived glutathione requires activity of glutamyl pyruvate transaminase 2, entry of glucose-derived pyruvate to mitochondria via alanine, and the glutamate exporter, SLC25A22. Glutathione derived from glucose maintains redox homeostasis in Cu-treated cells, reducing Cu-H 2 O 2 Fenton-like reaction mediated cell death. Progression of human ccRCC is associated with gene expression signature characterized by induction of ETC/OxPhos/GSH/Cu-related genes and decrease in HIF/glycolytic genes in subpopulations of cancer cells. Enhanced, concordant expression of genes related to ETC/OxPhos, GSH, and Cu characterizes metabolically active subpopulations of ccRCC cells in regions adjacent to proliferative subpopulations of ccRCC cells, implicating oxidative metabolism in supporting tumor growth.

DOI: https://doi.org/10.1101/2024.01.16.575895
Eur J Pharmacol. 2024 Jan 28. pii: S0014-2999(24)00022-0. [Epub ahead of print]966 176334

Farnesoid X receptor agonist tropifexor detoxifies ammonia by regulating the glutamine metabolism and urea cycles in cholestatic livers.

Yongtao Xiao, Weipeng Wang, Shicheng Peng, Ying Lu, Jun Du, Wei Cai.

  Hyperammonemia refers to elevated levels of ammonia in the blood, which is an important pathological feature of liver cirrhosis and hepatic failure. Preclinical studies suggest tropifexor (TXR), a novel non-bile acid agonist of Farnesoid X Receptor (FXR), has shown promising effects on reducing hepatic steatosis, inflammation, and fibrosis. This study evaluates the impact of TXR on hyperammonemia in a piglet model of cholestasis. We here observed blood ammonia significantly elevated in patients with biliary atresia (BA) and was positively correlated with liver injury. Targeted metabolomics and immunblotting showed glutamine metabolism and urea cycles were impaired in BA patients. Next, we observed that TXR potently suppresses bile duct ligation (BDL)-induced injuries in liver and brain with improving the glutamine metabolism and urea cycles. Within the liver, TXR enhances glutamine metabolism and urea cycles by up-regulation of key regulatory enzymes, including glutamine synthetase (GS), carbamoyl-phosphate synthetase 1 (CPS1), argininosuccinate synthetase (ASS1), argininosuccinate lyase (ASL), and arginase 1 (ARG1). In primary mice hepatocytes, TXR detoxified ammonia via increasing ureagenesis. Mechanically, TXR activating FXR to increase express enzymes that regulating ureagenesis and glutamine synthesis through a transcriptional approach. Together, these results suggest that TXR may have therapeutic implications for hyperammonemic conditions in cholestatic livers.

Keywords:  Ammonia; Cholestasis; FXR; Glutamine metabolism; Urea cycles

DOI:  https://doi.org/10.1016/j.ejphar.2024.176334
Free Radic Biol Med. 2024 Jan 26. pii: S0891-5849(24)00036-4. [Epub ahead of print]213 327-342

Enhancement of de novo lipogenesis by the IDH1 and IDH2-dependent reverse TCA cycle maintains the growth and angiogenic capacity of bone marrow-derived endothelial progenitor cells under hypoxia.

Qiwei He, Tiantian Yu, Junxiong Chen, Jianli Liang, Dongni Lin, Kaihao Yan, Zijing Xie, Yuqi Song, Zhenzhou Chen.

  BACKGROUND: Bone marrow-derived endothelial progenitor cells (EPCs) play a dynamic role in maintaining the structure and function of blood vessels. But how these cells maintain their growth and angiogenic capacity under bone marrow hypoxic niche is still unclear. This study aims to explore the mechanisms from a perspective of cellular metabolism.METHODS: XFe96 Extracellular Flux Analyzer was used to analyze the metabolic status of EPCs. Gas Chromatography-Mass Spectrometry (GC-MS) was used to trace the carbon movement of 13C-labeled glucose and glutamine under 1 % O2 (hypoxia) and ∼20 % O2 (normoxia). Moreover, RNA interference, targeting isocitrate dehydrogenase-1 (IDH1) and IDH2, was used to inhibit the reverse tricarboxylic acid (TCA) cycle and analyze metabolic changes via isotope tracing as well as changes in cell growth and angiogenic potential under hypoxia. The therapeutic potential of EPCs under hypoxia was investigated in the ischemic hindlimb model.
RESULTS: Compared with normoxic cells, hypoxic cells showed increased glycolysis and decreased mitochondrial respiration. Isotope metabolic tracing revealed that under hypoxia, the forward TCA cycle was decreased and the reverse TCA cycle was enhanced, mediating the conversion of α-ketoglutarate (α-KG) into isocitrate/citrate, and de novo lipid synthesis was promoted. Downregulation of IDH1 or IDH2 under hypoxia suppressed the reverse TCA cycle, attenuated de novo lipid synthesis (DNL), elevated α-KG levels, and decreased the expression of hypoxia inducible factor-1α (HIF-1α) and vascular endothelial growth factor A (VEGFA), eventually inhibiting the growth and angiogenic capacity of EPCs. Importantly, the transplantation of hypoxia-cultured EPCs in a mouse model of limb ischemia promoted new blood vessel regeneration and blood supply recovery in the ischemic area better than the transplantation of normoxia-cultured EPCs.
CONCLUSIONS: Under hypoxia, the IDH1- and IDH2-mediated reverse TCA cycle promotes glutamine-derived de novo lipogenesis and stabilizes the expression of α-KG and HIF-1α, thereby enhancing the growth and angiogenic capacity of EPCs.

Keywords:  Endothelial progenitor cells; HIF-1α; Hypoxia; Lipid synthesis; Reverse TCA cycle

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.01.028
J Hematol Oncol. 2024 Jan 31. 17(1): 6

Metabolic reprogramming in the tumor microenvironment of liver cancer.

Jian Lin, Dongning Rao, Mao Zhang, Qiang Gao.

  The liver is essential for metabolic homeostasis. The onset of liver cancer is often accompanied by dysregulated liver function, leading to metabolic rearrangements. Overwhelming evidence has illustrated that dysregulated cellular metabolism can, in turn, promote anabolic growth and tumor propagation in a hostile microenvironment. In addition to supporting continuous tumor growth and survival, disrupted metabolic process also creates obstacles for the anticancer immune response and restrains durable clinical remission following immunotherapy. In this review, we elucidate the metabolic communication between liver cancer cells and their surrounding immune cells and discuss how metabolic reprogramming of liver cancer impacts the immune microenvironment and the efficacy of anticancer immunotherapy. We also describe the crucial role of the gut-liver axis in remodeling the metabolic crosstalk of immune surveillance and escape, highlighting novel therapeutic opportunities.

Keywords:  Gut–liver axis; Immune microenvironment; Liver cancer; Metabolic reprogramming

DOI:  https://doi.org/10.1186/s13045-024-01527-8
BMC Genomics. 2024 Jan 30. 25(1): 125

A novel diabetic foot ulcer diagnostic model: identification and analysis of genes related to glutamine metabolism and immune infiltration.

Hongshuo Shi, Xin Yuan, Xiao Yang, Renyan Huang, Weijing Fan, Guobin Liu.

  BACKGROUND: Diabetic foot ulcer (DFU) is one of the most common and severe complications of diabetes, with vascular changes, neuropathy, and infections being the primary pathological mechanisms. Glutamine (Gln) metabolism has been found to play a crucial role in diabetes complications. This study aims to identify and validate potential Gln metabolism biomarkers associated with DFU through bioinformatics and machine learning analysis.METHODS: We downloaded two microarray datasets related to DFU patients from the Gene Expression Omnibus (GEO) database, namely GSE134431, GSE68183, and GSE80178. From the GSE134431 dataset, we obtained differentially expressed Gln-metabolism related genes (deGlnMRGs) between DFU and normal controls. We analyzed the correlation between deGlnMRGs and immune cell infiltration status. We also explored the relationship between GlnMRGs molecular clusters and immune cell infiltration status. Notably, WGCNA to identify differentially expressed genes (DEGs) within specific clusters. Additionally, we conducted GSVA to annotate enriched genes. Subsequently, we constructed and screened the best machine learning model. Finally, we validated the predictions' accuracy using a nomogram, calibration curves, decision curve analysis (DCA), and the GSE134431, GSE68183, and GSE80178 dataset.
RESULTS: In both the DFU and normal control groups, we confirmed the presence of deGlnMRGs and an activated immune response. From the GSE134431 dataset, we obtained 20 deGlnMRGs, including CTPS1, NAGS, SLC7A11, GGT1, GCLM, RIMKLA, ARG2, ASL, ASNS, ASNSD1, PPAT, GLS2, GLUD1, MECP2, ASS1, PRODH, CTPS2, ALDH5A1, DGLUCY, and SLC25A12. Furthermore, two clusters were identified in DFU. Immune infiltration analysis indicated the presence of immune heterogeneity in these two clusters. Additionally, we established a Support Vector Machine (SVM) model based on 5 genes (R3HCC1, ZNF562, MFN1, DRAM1, and PTGDS), which exhibited excellent performance on the external validation datasetGSE134431, GSE68183, and GSE80178 (AUC = 0.929).
CONCLUSION: This study has identified five Gln metabolism genes associated with DFU, revealing potential novel biomarkers and therapeutic targets for DFU. Additionally, the infiltration of immune-inflammatory cells plays a crucial role in the progression of DFU.

Keywords:  Diabetic foot ulcer; Gln metabolism; Immune infiltration; Machine learning; Molecular clusters

DOI:  https://doi.org/10.1186/s12864-024-10038-2
Biochimie. 2024 Jan 31. pii: S0300-9084(24)00036-1. [Epub ahead of print]

Should the standard model of cellular energy metabolism be reconsidered? Possible coupling between the pentose phosphate pathway, glycolysis and extra-mitochondrial oxidative phosphorylation.

Alessandro Maria Morelli, Felix Scholkmann.

  The process of cellular respiration occurs for energy production through catabolic reactions, generally with glucose as the first process step. In the present work, we introduce a novel concept for understanding this process, based on our conclusion that glucose metabolism is coupled to the pentose phosphate pathway (PPP) and extra-mitochondrial oxidative phosphorylation in a closed-loop process. According to the current standard model of glycolysis, glucose is first converted to glucose 6-phosphate (glucose 6-P) and then to fructose 6-phosphate, glyceraldehyde 3-phosphate and pyruvate, which then enters the Krebs cycle in the mitochondria. However, it is more likely that the pyruvate will be converted to lactate. In the PPP, glucose 6-P is branched off from glycolysis and used to produce NADPH and ribulose 5-phosphate (ribulose 5-P). Ribulose 5-P can be converted to fructose 6-P and glyceraldehyde 3-P. In our view, a circular process can take place in which the ribulose 5-P produced by the PPP enters the glycolysis pathway and is then retrogradely converted to glucose 6-P. This process is repeated several times until the complete degradation of glucose 6-P. The role of mitochondria in this process is to degrade lipids by beta-oxidation and produce acetyl-CoA; the function of producing ATP appears to be only secondary. This proposed new concept of cellular bioenergetics allows the resolution of some previously unresolved controversies related to cellular respiration and provides a deeper understanding of metabolic processes in the cell, including a new insights into the Warburg effect.

Keywords:  Cancer metabolism; Cellular respiration; Endoplasmic reticulum; Extra-mitochondrial OXPHOS; Glycolysis; Pentose phosphate pathway

DOI:  https://doi.org/10.1016/j.biochi.2024.01.018
Protein Sci. 2024 Feb;33(2): e4897

Distinct specificities of the HEMK2 protein methyltransferase in methylation of glutamine and lysine residues.

Sara Weirich, Gizem T Ulu, Thyagarajan T Chandrasekaran, Jana Kehl, Jasmin Schmid, Franziska Dorscht, Margarita Kublanovsky, Dan Levy, Albert Jeltsch.

  The HEMK2 protein methyltransferase has been described as glutamine methyltransferase catalyzing ERF1-Q185me1 and lysine methyltransferase catalyzing H4K12me1. Methylation of two distinct target residues is unique for this class of enzymes. To understand the specific catalytic adaptations of HEMK2 allowing it to master this chemically challenging task, we conducted a detailed investigation of the substrate sequence specificities of HEMK2 for Q- and K-methylation. Our data show that HEMK2 prefers methylation of Q over K at peptide and protein level. Moreover, the ERF1 sequence is strongly preferred as substrate over the H4K12 sequence. With peptide SPOT array methylation experiments, we show that Q-methylation preferentially occurs in a G-Q-X3 -R context, while K-methylation prefers S/T at the first position of the motif. Based on this, we identified novel HEMK2 K-methylation peptide substrates with sequences taken from human proteins which are methylated with high activity. Since H4K12 methylation by HEMK2 was very low, other protein lysine methyltransferases were examined for their ability to methylate the H4K12 site. We show that SETD6 has a high H4K12me1 methylation activity (about 1000-times stronger than HEMK2) and this enzyme is mainly responsible for H4K12me1 in DU145 prostate cancer cells.

Keywords:  H4K12me1; HEMK2; KMT9; SETD6; histone methylation; protein glutamine methylation; protein lysine methylation

DOI:  https://doi.org/10.1002/pro.4897
Cancer Lett. 2024 Jan 28. pii: S0304-3835(24)00064-8. [Epub ahead of print] 216671

The unfolded protein response-glutathione metabolism axis: A novel target of a cycloruthenated complexes bypassing tumor resistance mechanisms.

Gilles Riegel, Christophe Orvain, Sevda Recberlik, Marie-Elodie Spaety, Gernot Poschet, Aina Venkatasamy, Masami Yamamoto, Sachiyo Nomura, Tetsyua Tsukamoto, Murielle Masson, Isabelle Gross, Ronan Le Lagadec, Georg Mellitzer, Christian Gaiddon.

  Platinum-based drugs remain the reference treatment for gastric cancer (GC). However, the frequency of resistance, due to mutations in TP53 or alterations in the energy and redox metabolisms, impairs the efficacy of current treatments, highlighting the need for alternative therapeutic options. Here, we show that a cycloruthenated compound targeting the redox metabolism, RDC11, induces higher cytotoxicity than oxaliplatin in GC cells and is more potent in reducing tumor growth in vivo. Detailed investigations into the mode of action of RDC11 indicated that it targets the glutathione (GSH) metabolism, which is an important drug resistance mechanism. We demonstrate that cycloruthenated complexes regulate the expression of enzymes of the transsulfuration pathway via the Unfolded Protein Response (UPR) and its effector ATF4. Furthermore, RDC11 induces the expression of SLC7A11 encoding for the cystine/glutamate antiporter xCT. These effects lead to a lower cellular GSH content and elevated oxygen reactive species production, causing the activation of a caspase-independent apoptosis. Altogether, this study provides the first evidence that cycloruthenated complexes target the GSH metabolism, neutralizing thereby a major resistance mechanism towards platinum-based chemotherapies and anticancer immune response.

Keywords:  Caspase-independent apoptosis; ER stress; Glutathione; Metabolism; RDC11; Transsulfuration; UPR

DOI:  https://doi.org/10.1016/j.canlet.2024.216671
Heliyon. 2024 Jan 30. 10(2): e24454

Oncometabolite 2-hydroxyglutarate regulates anti-tumor immunity.

Mengyuan Cai, Jianyi Zhao, Qiang Ding, Jifu Wei.

  "Oncometabolite" 2-hydroxyglutarate (2-HG) is an aberrant metabolite found in tumor cells, exerting a pivotal influence on tumor progression. Recent studies have unveiled its impact on the proliferation, activation, and differentiation of anti-tumor T cells. Moreover, 2-HG regulates the function of innate immune components, including macrophages, dendritic cells, natural killer cells, and the complement system. Elevated levels of 2-HG hinder α-KG-dependent dioxygenases (α-KGDDs), contributing to tumorigenesis by disrupting epigenetic regulation, genome integrity, hypoxia-inducible factors (HIF) signaling, and cellular metabolism. The chiral molecular structure of 2-HG produces two enantiomers: D-2-HG and L-2-HG, each with distinct origins and biological functions. Efforts to inhibit D-2-HG and leverage the potential of L-2-HG have demonstrated efficacy in cancer immunotherapy. This review delves into the metabolism, biological functions, and impacts on the tumor immune microenvironment (TIME) of 2-HG, providing a comprehensive exploration of the intricate relationship between 2-HG and antitumor immunity. Additionally, we examine the potential clinical applications of targeted therapy for 2-HG, highlighting recent breakthroughs as well as the existing challenges.

Keywords:  2-Hydroxyglutarate; Isocitrate dehydrogenase; Oncometabolite; Therapeutic target; Tumor immune microenvironment

DOI:  https://doi.org/10.1016/j.heliyon.2024.e24454
Small. 2024 Feb 01. e2310300

Nanosensors Monitor Intracellular GSH Depletion: GSH Triggers Cu(II) for Tumor Imaging and Inhibition.

Yihan Wang, Ke Huang, Tingya Wang, Liu Liu, Fangfang Yu, Wenyu Sun, Wenyan Yao, Hongjie Xiong, Xiaohui Liu, Hui Jiang, Xuemei Wang.

  Glutathione (GSH) is the primary antioxidant in cells, and GSH consumption will break the redox balance in cells. Based on this, a method that uses high concentrations of GSH in the tumor microenvironment to trigger the redox reaction of Cu(II) to generate copper nanoprobes with fluorescence and tumor growth inhibition properties is proposed. The nanoprobe mainly exists in the form of Cu(I) and catalyzes the decomposition of hydrogen peroxide into hydroxyl radicals. At the same time, a simple and controllable carbon micro-nano electrode is used to construct a single-cell sensing platform, which enable the detection of glutathione content in single living cells after Cu(II) treatment, providing an excellent example for detecting single-cell biomolecules.

Keywords:  GSH depletion; TME response; biological imaging; nanosensor; tumor suppression

DOI:  https://doi.org/10.1002/smll.202310300