bims-glucam 2024-03-17 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024–03–17
seventeen papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine Supplementation as an Anticancer Strategy: A Potential Therapeutic Alternative to the Convention.
Hypoxia rewires glucose and glutamine metabolism in different sources of skeletal stem and progenitor cells similarly, except for pyruvate.
Mitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors.
Metabolic reprogramming of cancer cells by JMJD6-mediated pre-mRNA splicing associated with therapeutic response to splicing inhibitor.
Astrocyte-Neuron Interaction via the Glutamate-Glutamine Cycle and Its Dysfunction in Tau-Dependent Neurodegeneration.
A serine metabolic enzyme is flexing its muscle to help repair skeletal muscle.
Inversion of the Warburg Effect: Unraveling the Metabolic Nexus between Obesity and Cancer.
Metabolic phenotyping of healthy and diseased human RPE cells.
The Integrated Stress Response in metabolic adaptation.
Quantification of metabolic activity from isotope tracing data using automated methodology.
Restriction of Glycolysis Increases Serial Killing Capacity of Natural Killer Cells.
Hepatitis B virus e antigen induces atypical metabolism and differentially regulates programmed cell deaths of macrophages.
Advancing glioblastoma treatment by targeting metabolism.
Targeting the Warburg effect: A revisited perspective from molecular mechanisms to traditional and innovative therapeutic strategies in cancer.
Metabolic priming by multiple enzyme systems supports glycolysis, HIF1α stabilisation, and human cancer cell survival in early hypoxia.
Genetic and molecular characterization of metabolic pathway-based clusters in esophageal squamous cell carcinoma.
Glutathione Depletion-Induced ROS/NO Generation for Cascade Breast Cancer Therapy and Enhanced Anti-Tumor Immune Response.

Cancers (Basel). 2024 Mar 05. pii: 1057. [Epub ahead of print]16(5):

Glutamine Supplementation as an Anticancer Strategy: A Potential Therapeutic Alternative to the Convention.

Hayato Muranaka, Rasaq Akinsola, Sandrine Billet, Stephen J Pandol, Andrew E Hendifar, Neil A Bhowmick, Jun Gong.

  Glutamine, a multifaceted nonessential/conditionally essential amino acid integral to cellular metabolism and immune function, holds pivotal importance in the landscape of cancer therapy. This review delves into the intricate dynamics surrounding both glutamine antagonism strategies and glutamine supplementation within the context of cancer treatment, emphasizing the critical role of glutamine metabolism in cancer progression and therapy. Glutamine antagonism, aiming to disrupt tumor growth by targeting critical metabolic pathways, is challenged by the adaptive nature of cancer cells and the complex metabolic microenvironment, potentially compromising its therapeutic efficacy. In contrast, glutamine supplementation supports immune function, improves gut integrity, alleviates treatment-related toxicities, and improves patient well-being. Moreover, recent studies highlighted its contributions to epigenetic regulation within cancer cells and its potential to bolster anti-cancer immune functions. However, glutamine implementation necessitates careful consideration of potential interactions with ongoing treatment regimens and the delicate equilibrium between supporting normal cellular function and promoting tumorigenesis. By critically assessing the implications of both glutamine antagonism strategies and glutamine supplementation, this review aims to offer comprehensive insights into potential therapeutic strategies targeting glutamine metabolism for effective cancer management.

Keywords:  amino acids; cachexia; cancer; cancer therapy; glutamine; metabolism; nutrition

DOI:  https://doi.org/10.3390/cancers16051057
J Bone Miner Res. 2024 Jan 11. pii: zjad016. [Epub ahead of print]

Hypoxia rewires glucose and glutamine metabolism in different sources of skeletal stem and progenitor cells similarly, except for pyruvate.

Shauni Loopmans, Guillaume Tournaire, Ingrid Stockmans, Steve Stegen, Geert Carmeliet.

  Skeletal stem and progenitor cells (SSPCs) are crucial for bone development, homeostasis, and repair. SSPCs are considered to reside in a rather hypoxic niche in the bone, but distinct SSPC niches have been described in different skeletal regions, and they likely differ in oxygen and nutrient availability. Currently it remains unknown whether the different SSPC sources have a comparable metabolic profile and respond in a similar manner to hypoxia. In this study, we show that cell proliferation of all SSPCs was increased in hypoxia, suggesting that SSPCs can indeed function in a hypoxic niche in vivo. In addition, low oxygen tension increased glucose consumption and lactate production, but affected pyruvate metabolism cell-specifically. Hypoxia decreased tricarboxylic acid (TCA) cycle anaplerosis and altered glucose entry into the TCA cycle from pyruvate dehydrogenase to pyruvate carboxylase and/or malic enzyme. Finally, a switch from glutamine oxidation to reductive carboxylation was observed in hypoxia, as well as cell-specific adaptations in the metabolism of other amino acids. Collectively, our findings show that SSPCs from different skeletal locations proliferate adequately in hypoxia by rewiring glucose and amino acid metabolism in a cell-specific manner.

Keywords:  cell metabolism; chondrocyte; hypoxia; proliferation; skeletal progenitor

DOI:  https://doi.org/10.1093/jbmr/zjad016
Nat Commun. 2024 Mar 11. 15(1): 2203

Mitochondrial metabolism sustains CD8+ T cell migration for an efficient infiltration into solid tumors.

Luca Simula, Mattia Fumagalli, Lene Vimeux, Irena Rajnpreht, Philippe Icard, Gary Birsen, Dongjie An, Frédéric Pendino, Adrien Rouault, Nadège Bercovici, Diane Damotte, Audrey Lupo-Mansuet, Marco Alifano, Marie-Clotilde Alves-Guerra, Emmanuel Donnadieu.

The ability of CD8+ T cells to infiltrate solid tumors and reach cancer cells is associated with improved patient survival and responses to immunotherapy. Thus, identifying the factors controlling T cell migration in tumors is critical, so that strategies to intervene on these targets can be developed. Although interstitial motility is a highly energy-demanding process, the metabolic requirements of CD8+ T cells migrating in a 3D environment remain unclear. Here, we demonstrate that the tricarboxylic acid (TCA) cycle is the main metabolic pathway sustaining human CD8+ T cell motility in 3D collagen gels and tumor slices while glycolysis plays a more minor role. Using pharmacological and genetic approaches, we report that CD8+ T cell migration depends on the mitochondrial oxidation of glucose and glutamine, but not fatty acids, and both ATP and ROS produced by mitochondria are required for T cells to migrate. Pharmacological interventions to increase mitochondrial activity improve CD8+ T cell intratumoral migration and CAR T cell recruitment into tumor islets leading to better control of tumor growth in human xenograft models. Our study highlights the rationale of targeting mitochondrial metabolism to enhance the migration and antitumor efficacy of CAR T cells in treating solid tumors.

DOI: https://doi.org/10.1038/s41467-024-46377-7
Elife. 2024 Mar 15. pii: RP90993. [Epub ahead of print]12

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

Carolyn M 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 jumonji domain containing 6, arginine demethylase, and lysine hydroxylase, JMJD6, acts as a hub connecting splicing and metabolism in MYC-driven human neuroblastoma. JMJD6 cooperates with MYC in cellular transformation of murine neural crest cells 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 associated with alternative pre-mRNA splicing through JMJD6, providing a rationale to target JMJD6 as a therapeutic avenue for treating MYC-driven cancers.

Keywords:  GLS; JMJD6; cancer biology; indisulam; neuroblastoma; none; splicing

DOI:  https://doi.org/10.7554/eLife.90993
Int J Mol Sci. 2024 Mar 06. pii: 3050. [Epub ahead of print]25(5):

Astrocyte-Neuron Interaction via the Glutamate-Glutamine Cycle and Its Dysfunction in Tau-Dependent Neurodegeneration.

Marta Sidoryk-Węgrzynowicz, Kamil Adamiak, Lidia Strużyńska.

  Astroglia constitute the largest group of glial cells and are involved in numerous actions that are critical to neuronal development and functioning, such as maintaining the blood-brain barrier, forming synapses, supporting neurons with nutrients and trophic factors, and protecting them from injury. These properties are deeply affected in the course of many neurodegenerative diseases, including tauopathies, often before the onset of the disease. In this respect, the transfer of essential amino acids such as glutamate and glutamine between neurons and astrocytes in the glutamate-glutamine cycle (GGC) is one example. In this review, we focus on the GGC and the disruption of this cycle in tau-dependent neurodegeneration. A profound understanding of the complex functions of the GGC and, in the broader context, searching for dysfunctions in communication pathways between astrocytes and neurons via GGC in health and disease, is of critical significance for the development of novel mechanism-based therapies for neurodegenerative disorders.

Keywords:  astrocyte–neuron integrity; glutamate transporters; glutamate–glutamine cycle; glutamine transporters; tau-dependent neurodegeneration

DOI:  https://doi.org/10.3390/ijms25053050
Genes Dev. 2024 Mar 14.

A serine metabolic enzyme is flexing its muscle to help repair skeletal muscle.

Benjámin R Baráth, Laszlo Nagy.

  Metabolic reprogramming of stem cells is a targetable pathway to control regeneration. Activation of stem cells results in down-regulation of oxidative phosphorylation (OXPHOS) and fatty acid oxidation (FAO) and turns on glycolysis to provide fuel for proliferation and specific signaling events. How cell type-specific events are regulated is unknown. In this issue of Genes & Development Ciuffoli and colleagues (pp. XXX-XXX) use metabolomic, gene inactivation, and functional approaches to show that phosphoserine aminotransferase (Psat1), an enzyme in serine biosynthesis, is activated in muscle stem cells and contributes to cell expansion and skeletal muscle regeneration via the production of α-ketoglutarate and glutamine.

Keywords:  aging; glutamine; ketoglutarate; muscle regeneration; muscle stem cells

DOI:  https://doi.org/10.1101/gad.351666.124
ACS Pharmacol Transl Sci. 2024 Mar 08. 7(3): 560-569

Inversion of the Warburg Effect: Unraveling the Metabolic Nexus between Obesity and Cancer.

Reshmi Akter, Muhammad Awais, Vinothini Boopathi, Jong Chan Ahn, Deok Chun Yang, Se Chan Kang, Dong Uk Yang, Seok-Kyu Jung.

Obesity is a well-established risk factor for cancer, significantly impacting both cancer incidence and mortality. However, the intricate molecular mechanisms connecting adipose tissue to cancer cell metabolism are not fully understood. This Review explores the historical context of tumor energy metabolism research, tracing its origins to Otto Warburg's pioneering work in 1920. Warburg's discovery of the "Warburg effect", wherein cancer cells prefer anaerobic glycolysis even in the presence of oxygen, laid the foundation for understanding cancer metabolism. Building upon this foundation, the "reverse Warburg effect" emerged in 2009, elucidating the role of aerobic glycolysis in cancer-associated fibroblasts (CAFs) and its contribution to lactate accumulation in the tumor microenvironment, subsequently serving as a metabolic substrate for cancer cells. In contrast, within high-adiposity contexts, cancer cells exhibit a unique metabolic shift termed the "inversion of the Warburg effect". This phenomenon, distinct from the stromal-dependent reverse Warburg effect, relies on increased nutrient abundance in obesity environments, leading to the generation of glucose from lactate as a metabolic substrate. This Review underscores the heightened tumor proliferation and aggressiveness associated with obesity, introducing the "inversion of the Warburg effect" as a novel mechanism rooted in the altered metabolic landscape within an obese milieu. The insights presented here open promising avenues for therapeutic exploration, offering fresh perspectives and opportunities for the development of innovative cancer treatment strategies.

DOI: https://doi.org/10.1021/acsptsci.3c00301
bioRxiv. 2024 Mar 01. pii: 2024.02.28.582405. [Epub ahead of print]

Metabolic phenotyping of healthy and diseased human RPE cells.

Saira Rizwan, Beverly Toothman, Bo Li, Abbi J Engel, Rayne R Lim, Jinyu Lu, Jennifer R Chao, Jianhai Du.

Purpose: Metabolic defects in retinal pigment epithelium (RPE) are underlying many retinal degenerative diseases. This study aims to identify the nutrient requirements of healthy and diseased human RPE cells.
Methods: We profiled the utilization of 183 nutrients in human RPE cells: 1) differentiated and dedifferentiated fetal RPE (fRPE), 2) induced pluripotent stem cell derived-RPE (iPSC RPE), 3) Sorsby fundus dystrophy (SFD) patient-derived iPSC RPE and its CRISPR-corrected isogenic SFD (cSFD) iPSC RPE, and 5) ARPE-19 cell lines cultured under different conditions.
Results: Differentiated fRPE cells and healthy iPSC RPE cells can utilize 51 and 48 nutrients respectively, including sugars, intermediates from glycolysis and tricarboxylic acid (TCA) cycle, fatty acids, ketone bodies, amino acids, and dipeptides. However, when fRPE cells lose epithelial phenotype through dedifferentiated, they can only utilize 17 nutrients, primarily sugar and glutamine-related amino acids. SFD RPE cells can utilize 37 nutrients; however, Compared to cSFD RPE and healthy iPSC RPE, they are unable to utilize lactate, some TCA cycle intermediates, and short-chain fatty acids. Nonetheless, they show increased utilization of branch-chain amino acids (BCAAs) and BCAA-containing dipeptides. The dedifferentiated ARPE-19 cells in traditional culture media cannot utilize lactate and ketone bodies. In contrast, nicotinamide supplementation promotes differentiation into epithelial phenotype, restoring the ability to use these nutrients.
Conclusions: Epithelial phenotype confers metabolic flexibility to the RPE for utilizing various nutrients. SFD RPE cells have reduced metabolic flexibility, relying on the oxidation of BCAAs. Our findings highlight the importance of nutrient availability and utilization in RPE differentiation and diseases.

DOI: https://doi.org/10.1101/2024.02.28.582405
J Biol Chem. 2024 Mar 08. pii: S0021-9258(24)01646-6. [Epub ahead of print] 107151

The Integrated Stress Response in metabolic adaptation.

Hyung Don Ryoo.

  The Integrated Stress Response (ISR) refers to signaling pathways initiated by stress-activated eIF2‹ kinases. Distinct eIF2‹ kinases respond to different stress signals, including amino acid deprivation and mitochondrial stress. Such stress-induced eIF2‹ phosphorylation attenuates general mRNA translation and, at the same time, stimulates the preferential translation of specific downstream factors to orchestrate an adaptive gene expression program. In recent years, there have been significant new advances in our understanding of ISR during metabolic stress adaptation. Here, I discuss those advances, reviewing among others the ISR activation mechanisms in response to amino acid deprivation and mitochondrial stress. In addition, I review how ISR regulates the amino acid metabolic pathways and how changes in the ISR impact the physiology and pathology of various disease models.

Keywords:  ATF4; GCN1; GCN2; HRI; Integrated Stress Response; amino acid deprivation; cysteine; eIF2‹; glutathione; mitochondrial stress; serine biosynthesis

DOI:  https://doi.org/10.1016/j.jbc.2024.107151
bioRxiv. 2024 Feb 28. pii: 2024.02.25.581907. [Epub ahead of print]

Quantification of metabolic activity from isotope tracing data using automated methodology.

Shiyu Liu, Xiaojing Liu, Jason W Locasale.

Isotope tracing is a widely used technique to study metabolic activities by introducing heavy labeled nutrients into living cells and organisms. However, interpreting isotope tracing data is often heuristic, and application of automated methods using artificial intelligence is limited due to the paucity of evaluative knowledge. Our study developed a new pipeline that efficiently predicts metabolic activity in expansive metabolic networks and systematically quantifies flux uncertainty of traditional computational methods. We further developed an algorithm adept at significantly reducing this uncertainty, enabling robust evaluations of metabolic activity with limited data. Using this technology, we discovered highly reprogrammed mitochondria-cytosol exchange cycles in tumor tissue of patients, and observed similar metabolic patterns influenced by nutritional conditions in cancer cells. Thus, our refined methodology provides robust automated quantification of metabolism allowing for new insight into metabolic network activity.

DOI: https://doi.org/10.1101/2024.02.25.581907
Int J Mol Sci. 2024 Mar 02. pii: 2917. [Epub ahead of print]25(5):

Restriction of Glycolysis Increases Serial Killing Capacity of Natural Killer Cells.

Lea Katharina Picard, Jens Alexander Niemann, Elisabeth Littwitz-Salomon, Herbert Waldmann, Carsten Watzl.

  Tumor cells rely heavily on glycolysis to meet their high metabolic demands. While this results in nutrient deprivation within the tumor microenvironment and has negative effects on infiltrating immune cells such as natural killer (NK) cells, it also creates a potential target for cancer therapies. Here we use Glupin, an inhibitor of glucose transporters, to study the effect of limited glucose uptake on NK cells and their anti-tumor functions. Glupin treatment effectively inhibited glucose uptake and restricted glycolysis in NK cells. However, acute treatment had no negative effect on NK cell cytotoxicity or cytokine production. Long-term restriction of glucose uptake via Glupin treatment only delayed NK cell proliferation, as they could switch to glutaminolysis as an alternative energy source. While IFN-γ production was partially impaired, long-term Glupin treatment had no negative effect on degranulation. Interestingly, the serial killing activity of NK cells was even slightly enhanced, possibly due to changes in NAD metabolism. This demonstrates that NK cell cytotoxicity is remarkably robust and insensitive to metabolic disturbances, which makes cellular metabolism an attractive target for immune-mediated tumor therapies.

Keywords:  cytokines; cytotoxicity; degranulation; glucose transporter; metabolism

DOI:  https://doi.org/10.3390/ijms25052917
PLoS Pathog. 2024 Mar 11. 20(3): e1012079

Hepatitis B virus e antigen induces atypical metabolism and differentially regulates programmed cell deaths of macrophages.

Yumei Li, Christine Wu, Jiyoung Lee, Qiqi Ning, Juhyeon Lim, Hyungjin Eoh, Sean Wang, Benjamin P Hurrell, Omid Akbari, Jing-Hsiung James Ou.

Macrophages can undergo M1-like proinflammatory polarization with low oxidative phosphorylation (OXPHOS) and high glycolytic activities or M2-like anti-inflammatory polarization with the opposite metabolic activities. Here we show that M1-like macrophages induced by hepatitis B virus (HBV) display high OXPHOS and low glycolytic activities. This atypical metabolism induced by HBV attenuates the antiviral response of M1-like macrophages and is mediated by HBV e antigen (HBeAg), which induces death receptor 5 (DR5) via toll-like receptor 4 (TLR4) to induce death-associated protein 3 (DAP3). DAP3 then induces the expression of mitochondrial genes to promote OXPHOS. HBeAg also enhances the expression of glutaminases and increases the level of glutamate, which is converted to α-ketoglutarate, an important metabolic intermediate of the tricarboxylic acid cycle, to promote OXPHOS. The induction of DR5 by HBeAg leads to apoptosis of M1-like and M2-like macrophages, although HBeAg also induces pyroptosis of the former. These findings reveal novel activities of HBeAg, which can reprogram mitochondrial metabolism and trigger different programmed cell death responses of macrophages depending on their phenotypes to promote HBV persistence.

DOI: https://doi.org/10.1371/journal.ppat.1012079
Neoplasia. 2024 Mar 12. pii: S1476-5586(24)00022-8. [Epub ahead of print]51 100985

Advancing glioblastoma treatment by targeting metabolism.

Jinyi Zhao, Xuemei Ma, Peixian Gao, Xueqi Han, Pengxiang Zhao, Fei Xie, Mengyu Liu.

  Alterations in cellular metabolism are important hallmarks of glioblastoma(GBM). Metabolic reprogramming is a critical feature as it meets the higher nutritional demand of tumor cells, including proliferation, growth, and survival. Many genes, proteins, and metabolites associated with GBM metabolism reprogramming have been found to be aberrantly expressed, which may provide potential targets for cancer treatment. Therefore, it is becoming increasingly important to explore the role of internal and external factors in metabolic regulation in order to identify more precise therapeutic targets and diagnostic markers for GBM. In this review, we define the metabolic characteristics of GBM, investigate metabolic specificities such as targetable vulnerabilities and therapeutic resistance, as well as present current efforts to target GBM metabolism to improve the standard of care.

Keywords:  Glioblastoma; Metabolism; Signaling pathway; Therapy

DOI:  https://doi.org/10.1016/j.neo.2024.100985
Acta Pharm Sin B. 2024 Mar;14(3): 953-1008

Targeting the Warburg effect: A revisited perspective from molecular mechanisms to traditional and innovative therapeutic strategies in cancer.

Minru Liao, Dahong Yao, Lifeng Wu, Chaodan Luo, Zhiwen Wang, Jin Zhang, Bo Liu.

  Cancer reprogramming is an important facilitator of cancer development and survival, with tumor cells exhibiting a preference for aerobic glycolysis beyond oxidative phosphorylation, even under sufficient oxygen supply condition. This metabolic alteration, known as the Warburg effect, serves as a significant indicator of malignant tumor transformation. The Warburg effect primarily impacts cancer occurrence by influencing the aerobic glycolysis pathway in cancer cells. Key enzymes involved in this process include glucose transporters (GLUTs), HKs, PFKs, LDHs, and PKM2. Moreover, the expression of transcriptional regulatory factors and proteins, such as FOXM1, p53, NF-κB, HIF1α, and c-Myc, can also influence cancer progression. Furthermore, lncRNAs, miRNAs, and circular RNAs play a vital role in directly regulating the Warburg effect. Additionally, gene mutations, tumor microenvironment remodeling, and immune system interactions are closely associated with the Warburg effect. Notably, the development of drugs targeting the Warburg effect has exhibited promising potential in tumor treatment. This comprehensive review presents novel directions and approaches for the early diagnosis and treatment of cancer patients by conducting in-depth research and summarizing the bright prospects of targeting the Warburg effect in cancer.

Keywords:  Cancer; Drug resistance; LncRNAs; Regulatory factor; Small-molecule drug; Traditional Chinese medicine; Warburg effect; miRNAs

DOI:  https://doi.org/10.1016/j.apsb.2023.12.003
EMBO J. 2024 Mar 14.

Metabolic priming by multiple enzyme systems supports glycolysis, HIF1α stabilisation, and human cancer cell survival in early hypoxia.

Fiona Grimm, Agustín Asuaje, Aakriti Jain, Mariana Silva Dos Santos, Jens Kleinjung, Patrícia M Nunes, Stefanie Gehrig, Louise Fets, Salihanur Darici, James I MacRae, Dimitrios Anastasiou.

  Adaptation to chronic hypoxia occurs through changes in protein expression, which are controlled by hypoxia-inducible factor 1α (HIF1α) and are necessary for cancer cell survival. However, the mechanisms that enable cancer cells to adapt in early hypoxia, before the HIF1α-mediated transcription programme is fully established, remain poorly understood. Here we show in human breast cancer cells, that within 3 h of hypoxia exposure, glycolytic flux increases in a HIF1α-independent manner but is limited by NAD+ availability. Glycolytic ATP maintenance and cell survival in early hypoxia rely on reserve lactate dehydrogenase A capacity as well as the activity of glutamate-oxoglutarate transaminase 1 (GOT1), an enzyme that fuels malate dehydrogenase 1 (MDH1)-derived NAD+. In addition, GOT1 maintains low α-ketoglutarate levels, thereby limiting prolyl hydroxylase activity to promote HIF1α stabilisation in early hypoxia and enable robust HIF1α target gene expression in later hypoxia. Our findings reveal that, in normoxia, multiple enzyme systems maintain cells in a primed state ready to support increased glycolysis and HIF1α stabilisation upon oxygen limitation, until other adaptive processes that require more time are fully established.

Keywords:  Glycolysis; HIF1α; Hypoxia; Metabolism; α-Ketoglutarate

DOI:  https://doi.org/10.1038/s44318-024-00065-w
Sci Rep. 2024 Mar 14. 14(1): 6200

Genetic and molecular characterization of metabolic pathway-based clusters in esophageal squamous cell carcinoma.

Ze Wang, Yuan Zhang, Xiaorong Yang, Tongchao Zhang, Zhen Li, Yang Zhong, Yuan Fang, Wei Chong, Hao Chen, Ming Lu.

Esophageal squamous cell carcinoma (ESCC) is one of the most aggressive types of squamous cell carcinoma and represents a significant proportion of esophageal cancer. Metabolic reprogramming plays a key role in the occurrence and development of ESCC. Unsupervised clustering analysis was employed to stratify ESCC samples into three clusters: MPC1-lipid type, MPC2-amino acid type, and MPC3-energy type, based on the enrichment scores of metabolic pathways extracted from the Reactome database. The MPC3 cluster exhibited characteristics of energy metabolism, with heightened glycolysis, cofactors, and nucleotide metabolism, showing a trend toward increased aggressiveness and poorer survival rates. On the other hand, MPC1 and MPC2 primarily involved lipid and amino acid metabolism, respectively. In addition, liquid chromatography‒mass spectrometry-based metabolite profiles and potential therapeutic agents were explored and compared among ESCC cell lines with different MPCs. MPC3 amplified energy metabolism markers, especially carnitines. In contrast, MPC1 and MPC2 predominantly had elevated levels of lipids (primarily triacylglycerol) and amino acids, respectively. Furthermore, MPC3 demonstrated a suboptimal clinical response to PD-L1 immunotherapy but showed increased sensitivity to the doramapimod chemotherapy regimen, as evident from drug sensitivity evaluations. These insights pave the way for a more personalized therapeutic approach, potentially enhancing treatment precision for ESCC patients.

DOI: https://doi.org/10.1038/s41598-024-56391-w
Int J Nanomedicine. 2024 ;19 2301-2315

Glutathione Depletion-Induced ROS/NO Generation for Cascade Breast Cancer Therapy and Enhanced Anti-Tumor Immune Response.

Jing Wang, Yanxiang Sang, Weijian Chen, Liang Cheng, Wenxiang Du, Hongjie Zhang, Benyan Zheng, Lei Song, Yuan Hu, Xiaopeng Ma.

   Introduction: As an effective alternative choice to traditional mono-therapy, multifunctional nanoplatforms hold great promise for cancer therapy. Based on the strategies of Fenton-like reactions and reactive oxygen species (ROS)-mediated therapy, black phosphorus (BP) nanoplatform BP@Cu2O@L-Arg (BCL) co-assembly of cuprous oxide (Cu2O) and L-Arginine (L-Arg) nanoparticles was developed and evaluated for synergistic cascade breast cancer therapy.
Methods: Cu2O particles were generated in situ on the surface of the BP nanosheets, followed by L-Arg incorporation through electrostatic interactions. In vitro ROS/nitric oxide (NO) generation and glutathione (GSH) depletion were evaluated. In vitro and in vivo anti-cancer activity were also assessed. Finally, immune response of BCL under ultrasound was investigated.
Results: Cu2O was incorporated into BP to exhaust the overexpressed intracellular GSH in cancer cells via the Fenton reaction, thereby decreasing ROS consumption. Apart from being used as biocompatible carriers, BP nanoparticles served as sonosensitizers to produce excessive ROS under ultrasound irradiation. The enhanced ROS accumulation accelerated the oxidation of L-Arg, which further promoted NO generation for gas therapy. In vitro experiments revealed the outstanding therapeutic killing effects of BCL under ultrasound via mechanisms involving GSH deletion and excessive ROS and NO generation. In vivo studies have illustrated that the nanocomplex modified the immune response by promoting macrophage and CD8+ cell infiltration and inhibiting MDSC infiltration.
Discussion: BCL nanoparticles exhibited multifunctional characteristics for GSH depletion-induced ROS/NO generation, making a new multitherapy strategy for cascade breast cancer therapy.

Keywords:  black phosphorus; chemodynamic therapy; combination cancer therapy; nitric oxide gas therapy; sonodynamic therapy

DOI:  https://doi.org/10.2147/IJN.S440709