bims-glucam 2024-07-14 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024–07–14
twenty-one papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine metabolism improves left ventricular function but not macrophage-mediated inflammation following myocardial infarction.
MRPL35 Induces Proliferation, Invasion, and Glutamine Metabolism in NSCLC Cells by Upregulating SLC7A5 Expression.
Deciphering glutamine metabolism patterns for malignancy and tumor microenvironment in clear cell renal cell carcinoma.
Origin and Roles of Alanine and Glutamine in Gluconeogenesis in the Liver, Kidneys, and Small Intestine under Physiological and Pathological Conditions.
Metabolic Vulnerabilities in Cancer: A New Therapeutic Strategy.
Is Cancer Metabolism an Atavism?
Therapeutic implications of the metabolic changes associated with BRAF inhibition in melanoma.
Importance of Michaelis Constants for Cancer Cell Redox Balance and Lactate Secretion-Revisiting the Warburg Effect.
Glutamine metabolic competition drives immunosuppressive reprogramming of intratumour GPR109A+ myeloid cells to promote liver cancer progression.
Glucose-6-phosphate dehydrogenase maintains redox homeostasis and biosynthesis in LKB1-deficient KRAS-driven lung cancer.
Metabolic profiling and combined therapeutic strategies unveil the cytotoxic potential of selenium-chrysin (SeChry) in NSCLC cells.
Unveiling the impact of glutathione (GSH) and p53 gene deletion on tumor cell metabolism by amino acid and proteomics analysis.
Metabolic reprogramming in esophageal squamous cell carcinoma.
Curcumin synergistically enhances the efficacy of gemcitabine against gemcitabine-resistant cholangiocarcinoma via the targeting LAT2/glutamine pathway.
CD39 is induced by nutrient deprivation in colorectal cancer cells and contributes to the tolerance to hypoxia.
Pan-Cancer, Genome-Scale Metabolic Network Analysis of over 10,000 Patients Elucidates Relationship between Metabolism and Survival.
Overcoming Cancer Persister Cells by Stabilizing the ATF4 Promoter G-quadruplex.
Norovirus NS1/2 protein increases glutaminolysis for efficient viral replication.
A novel amino acid metabolism-related gene signature to predict the overall survival of esophageal squamous cell carcinoma patients.
Metabolic Profiling of Cochlear Organoids Identifies α-Ketoglutarate and NAD+ as Limiting Factors for Hair Cell Reprogramming.
Usefulness of Perioperative Nutritional Therapy with the Glutamine/Arginine/Calcium β-Hydroxy-β-Methylbutyrate Product in Esophageal Cancer Surgery: A Single-Center Retrospective Study.

Am J Physiol Cell Physiol. 2024 Jul 09.

Glutamine metabolism improves left ventricular function but not macrophage-mediated inflammation following myocardial infarction.

Alan J Mouton, Nikaela M Aitken, Jemylle G Morato, Jussara M do Carmo, Alexandre A da Silva, Ana C Omoto, Xuan Li, Zhen Wang, Alexandra C Schrimpe-Rutledge, Simona G Codreanu, Stacy D Sherrod, John A McLean, Joshua K Stanford, Jordan A Brown, John E Hall.

  Glutamine is a critical amino acid that serves as an energy source, building block, and signaling molecule for the heart tissue and the immune system. However, the role of glutamine metabolism in regulating cardiac remodeling following myocardial infarction (MI) is unknown. In this study, we show in adult male mice that glutamine metabolism is altered both in the remote (contractile) area and in infiltrating macrophages in the infarct area after permanent left anterior descending artery occlusion. We found that metabolites related to glutamine metabolism were differentially altered in macrophages at days 1, 3, and 7 after MI using untargeted metabolomics. Glutamine metabolism in live cells was increased after MI relative to no MI controls. Gene expression in the remote area of the heart indicated a loss of glutamine metabolism. Glutamine administration improved LV function at days 1, 3, and 7 after MI, which was associated with improved contractile and metabolic gene expression. Conversely, administration of BPTES, a pharmacological inhibitor of glutaminase-1, worsened LV function after MI. Neither glutamine nor BPTES administration impacted gene expression or bioenergetics of macrophages isolated from the infarct area. Our results indicate that glutamine metabolism plays a critical role in maintaining LV contractile function following MI, and that glutamine administration improves LV function. Glutamine metabolism may also play a role in regulating macrophage function, but macrophages are not responsive to exogenous pharmacological manipulation of glutamine metabolism.

Keywords:  cardiac remodeling; glutamine; heart failure; immunometabolism; macrophage

DOI:  https://doi.org/10.1152/ajpcell.00272.2024
Clin Respir J. 2024 Jul;18(7): e13799

MRPL35 Induces Proliferation, Invasion, and Glutamine Metabolism in NSCLC Cells by Upregulating SLC7A5 Expression.

Wei Hou, Juan Chen, Yaoyuan Wang.

   BACKGROUND: Mitochondrial ribosomal protein L35 (MRPL35) has been reported to contribute to the growth of non-small cell lung cancer (NSCLC) cells. However, the functions and mechanisms of MRPL35 on glutamine metabolism in NSCLC remain unclear.
METHODS: The detection of mRNA and protein of MRPL35, ubiquitin-specific protease 39 (USP39), and solute carrier family 7 member 5 (SLC7A5) was conducted using qRT-PCR and western blotting. Cell proliferation, apoptosis, and invasion were evaluated using the MTT assay, EdU assay, flow cytometry, and transwell assay, respectively. Glutamine metabolism was analyzed by detecting glutamine consumption, α-ketoglutarate level, and glutamate production. Cellular ubiquitination analyzed the deubiquitination effect of USP39 on MRPL35. An animal experiment was conducted for in vivo analysis.
RESULTS: MRPL35 was highly expressed in NSCLC tissues and cell lines, and high MRPL35 expression predicted poor outcome in NSCLC patients. In vitro analyses suggested that MRPL35 knockdown suppressed NSCLC cell proliferation, invasion, and glutamine metabolism. Moreover, MRPL35 silencing hindered tumor growth in vivo. Mechanistically, USP39 stabilized MRPL35 expression by deubiquitination and then promoted NSCLC cell proliferation, invasion, and glutamine metabolism. In addition, MRPL35 positively affected SLC7A5 expression in NSCLC cells in vitro and in vivo. Moreover, the anticancer effects of MRPL35 silencing could be rescued by SLC7A5 overexpression in NSCLC cells.
CONCLUSION: MRPL35 expression was stabilized by USP39-induced deubiquitination in NSCLC cells, and knockdown of MRPL35 suppressed NSCLC cell proliferation, invasion, and glutamine metabolism in vitro and impeded tumor growth in vivo by upregulating SLC7A5, providing a promising therapeutic target for NSCLC.

Keywords:  MRPL35; SLC7A5; USP39; deubiquitination; glutamine metabolism

DOI:  https://doi.org/10.1111/crj.13799
Clin Exp Med. 2024 Jul 06. 24(1): 152

Deciphering glutamine metabolism patterns for malignancy and tumor microenvironment in clear cell renal cell carcinoma.

Gengrun Wu, Teng Li, Yuanbiao Chen, Shiqi Ye, Siqi Zhou, Xi Tian, Aihetaimujiang Anwaier, Shuxuan Zhu, Wenhao Xu, Xiaohang Hao, Dingwei Ye, Hailiang Zhang.

  Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney cancer characterized by metabolic reprogramming. Glutamine metabolism is pivotal in metabolic reprogramming, contributing to the significant heterogeneity observed in ccRCC. Consequently, developing prognostic markers associated with glutamine metabolism could enhance personalized treatment strategies for ccRCC patients. This study obtained RNA sequencing and clinical data from 763 ccRCC cases sourced from multiple databases. Consensus clustering of 74 glutamine metabolism related genes (GMRGs)- profiles stratified the patients into three clusters, each of which exhibited distinct prognosis, tumor microenvironment, and biological characteristics. Then, six genes (SMTNL2, MIOX, TMEM27, SLC16A12, HRH2, and SAA1) were identified by machine-learning algorithms to develop a predictive signature related to glutamine metabolism, termed as GMRScore. The GMRScore showed significant differences in clinical prognosis, expression profile of immune checkpoints, abundance of immune cells, and immunotherapy response of ccRCC patients. Besides, the nomogram incorporating the GMRScore and clinical features showed strong predictive performance in prognosis of ccRCC patients. ALDH18A1, one of the GRMGs, exhibited elevated expression level in ccRCC and was related to markedly poorer prognosis in the integrated cohort, validated by proteomic profiling of 232 ccRCC samples from Fudan University Shanghai Cancer Center (FUSCC). Conducting western blotting, CCK-8, transwell, and flow cytometry assays, we found the knockdown of ALDH18A1 in ccRCC significantly promoted apoptosis and inhibited proliferation, invasion, and epithelial-mesenchymal transition (EMT) in two human ccRCC cell lines (786-O and 769-P). In conclusion, we developed a glutamine metabolism-related prognostic signature in ccRCC, which is tightly linked to the tumor immune microenvironment and immunotherapy response, potentially facilitating precision therapy for ccRCC patients. Additionally, this study revealed the key role of ALDH18A1 in promoting ccRCC progression for the first time.

Keywords:  ALDH18A1; Clear cell renal cell carcinoma; Glutamine metabolism; Immunotherapy response; Prognosis; Tumor microenvironment

DOI:  https://doi.org/10.1007/s10238-024-01390-4
Int J Mol Sci. 2024 Jun 27. pii: 7037. [Epub ahead of print]25(13):

Origin and Roles of Alanine and Glutamine in Gluconeogenesis in the Liver, Kidneys, and Small Intestine under Physiological and Pathological Conditions.

Milan Holeček.

  Alanine and glutamine are the principal glucogenic amino acids. Most originate from muscles, where branched-chain amino acids (valine, leucine, and isoleucine) are nitrogen donors and, under exceptional circumstances, a source of carbons for glutamate synthesis. Glutamate is a nitrogen source for alanine synthesis from pyruvate and a substrate for glutamine synthesis by glutamine synthetase. The following differences between alanine and glutamine, which can play a role in their use in gluconeogenesis, are shown: (i) glutamine appearance in circulation is higher than that of alanine; (ii) the conversion to oxaloacetate, the starting substance for glucose synthesis, is an ATP-consuming reaction for alanine, which is energetically beneficial for glutamine; (iii) most alanine carbons, but not glutamine carbons, originate from glucose; and (iv) glutamine acts a substrate for gluconeogenesis in the liver, kidneys, and intestine, whereas alanine does so only in the liver. Alanine plays a significant role during early starvation, exposure to high-fat and high-protein diets, and diabetes. Glutamine plays a dominant role in gluconeogenesis in prolonged starvation, acidosis, liver cirrhosis, and severe illnesses like sepsis and acts as a substrate for alanine synthesis in the small intestine. Interactions among muscles and the liver, kidneys, and intestine ensuring optimal alanine and glutamine supply for gluconeogenesis are suggested.

Keywords:  branched-chain amino acids; cirrhosis; diabetes; glucose; starvation

DOI:  https://doi.org/10.3390/ijms25137037
Crit Rev Oncol Hematol. 2024 Jul 06. pii: S1040-8428(24)00181-1. [Epub ahead of print] 104438

Metabolic Vulnerabilities in Cancer: A New Therapeutic Strategy.

Mohamed El-Tanani, Syed Arman Rabbani, Yahia El-Tanani, Ismail I Matalka.

  Cancer metabolism is now a key area for therapeutic intervention, targeting unique metabolic reprogramming crucial for tumor growth and survival. This article reviews the therapeutic potential of addressing metabolic vulnerabilities through glycolysis and glutaminase inhibitors, which disrupt cancer cell metabolism. Challenges such as tumor heterogeneity and adaptive resistance are discussed, with strategies including personalized medicine and predictive biomarkers to enhance treatment efficacy. Additionally, integrating diet and lifestyle changes with metabolic targeting underscores a holistic approach to improving therapy outcomes. The article also examines the benefits of incorporating these strategies into standard care, highlighting the potential for more tailored, safer treatments. In conclusion, exploiting metabolic vulnerabilities promises a new era in oncology, positioning metabolic targeting at the forefront of personalized cancer therapy and transforming patient care.

Keywords:  Adaptive resistance; Cancer metabolism; Glutaminase inhibitors; Glycolysis inhibitors; Metabolic reprogramming; Personalized medicine; Predictive biomarkers; Tumor heterogeneity

DOI:  https://doi.org/10.1016/j.critrevonc.2024.104438
Cancers (Basel). 2024 Jun 29. pii: 2415. [Epub ahead of print]16(13):

Is Cancer Metabolism an Atavism?

Eric Fanchon, Angélique Stéphanou.

  The atavistic theory of cancer posits that cancer emerges and progresses through the reversion of cellular phenotypes to more ancestral types with genomic and epigenetic changes deactivating recently evolved genetic modules and activating ancient survival mechanisms. This theory aims at explaining the known cancer hallmarks and the paradox of cancer's predictable progression despite the randomness of genetic mutations. Lineweaver and colleagues recently proposed the Serial Atavism Model (SAM), an enhanced version of the atavistic theory, which suggests that cancer progression involves multiple atavistic reversions where cells regress through evolutionary stages, losing recently evolved traits first and reactivating primitive ones later. The Warburg effect, where cancer cells upregulate glycolysis and lactate production in the presence of oxygen instead of using oxidative phosphorylation, is one of the key feature of the SAM. It is associated with the metabolism of ancient cells living on Earth before the oxygenation of the atmosphere. This review addresses the question of whether cancer metabolism can be considered as an atavistic reversion. By analyzing several known characteristics of cancer metabolism, we reach the conclusion that this version of the atavistic theory does not provide an adequate conceptual frame for cancer research. Cancer metabolism spans a whole spectrum of metabolic states which cannot be fully explained by a sequential reversion to an ancient state. Moreover, we interrogate the nature of cancer metabolism and discuss its characteristics within the framework of the SAM.

Keywords:  Warburg effect; cancer theory; gene expression; hypoxia; metabolic plasticity

DOI:  https://doi.org/10.3390/cancers16132415
Cancer Treat Rev. 2024 Jun 28. pii: S0305-7372(24)00123-3. [Epub ahead of print]129 102795

Therapeutic implications of the metabolic changes associated with BRAF inhibition in melanoma.

Alexander W Loftus, Mehrdad Zarei, Hanna Kakish, Omid Hajihassani, Jonathan J Hue, Christina Boutros, Hallie J Graor, Faith Nakazzi, Tsegaw Bahlibi, Jordan M Winter, Luke D Rothermel.

  Melanoma metabolism can be reprogrammed by activating BRAF mutations. These mutations are present in up to 50% of cutaneous melanomas, with the most common being V600E. BRAF mutations augment glycolysis to promote macromolecular synthesis and proliferation. Prior to the development of targeted anti-BRAF therapies, these mutations were associated with accelerated clinical disease in the metastatic setting. Combination BRAF and MEK inhibition is a first line treatment option for locally advanced or metastatic melanoma harboring targetable BRAF mutations. This therapy shows excellent response rates but these responses are not durable, with almost all patients developing resistance. When BRAF mutated melanoma cells are inhibited with targeted therapies the metabolism of those cells also changes. These cells rely less on glycolysis for energy production, and instead shift to a mitochondrial phenotype with upregulated TCA cycle activity and oxidative phosphorylation. An increased dependence on glutamine utilization is exhibited to support TCA cycle substrates in this metabolic rewiring of BRAF mutated melanoma. Herein we describe the relevant core metabolic pathways modulated by BRAF inhibition. These adaptive pathways represent vulnerabilities that could be targeted to overcome resistance to BRAF inhibitors. This review evaluates current and future therapeutic strategies that target metabolic reprogramming in melanoma cells, particularly in response to BRAF inhibition.

Keywords:  Amino acid; BRAF; Fatty acid; Glycolysis; Melanoma; Metabolic reprogramming; Mitochondria; Novel therapies; Oxidative phosphorylation; Resistance; Targeted therapies

DOI:  https://doi.org/10.1016/j.ctrv.2024.102795
Cancers (Basel). 2024 Jun 21. pii: 2290. [Epub ahead of print]16(13):

Importance of Michaelis Constants for Cancer Cell Redox Balance and Lactate Secretion-Revisiting the Warburg Effect.

Michael Niepmann.

  Cancer cells metabolize a large fraction of glucose to lactate, even under a sufficient oxygen supply. This phenomenon-the "Warburg Effect"-is often regarded as not yet understood. Cancer cells change gene expression to increase the uptake and utilization of glucose for biosynthesis pathways and glycolysis, but they do not adequately up-regulate the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS). Thereby, an increased glycolytic flux causes an increased production of cytosolic NADH. However, since the corresponding gene expression changes are not neatly fine-tuned in the cancer cells, cytosolic NAD+ must often be regenerated by loading excess electrons onto pyruvate and secreting the resulting lactate, even under sufficient oxygen supply. Interestingly, the Michaelis constants (KM values) of the enzymes at the pyruvate junction are sufficient to explain the priorities for pyruvate utilization in cancer cells: 1. mitochondrial OXPHOS for efficient ATP production, 2. electrons that exceed OXPHOS capacity need to be disposed of and secreted as lactate, and 3. biosynthesis reactions for cancer cell growth. In other words, a number of cytosolic electrons need to take the "emergency exit" from the cell by lactate secretion to maintain the cytosolic redox balance.

Keywords:  KM value; Michaelis constant; Warburg effect; aerobic glycolysis; anaerobic; cancer; glucose; lactate; lactic acid; pyruvate; tumor

DOI:  https://doi.org/10.3390/cancers16132290
Gut. 2024 Jul 09. pii: gutjnl-2024-332429. [Epub ahead of print]

Glutamine metabolic competition drives immunosuppressive reprogramming of intratumour GPR109A+ myeloid cells to promote liver cancer progression.

Yang Yang, Tianduo Pei, Chaobao Liu, Mingtao Cao, Xiaolin Hu, Jie Yuan, Fengqian Chen, Bao Guo, Yuemei Hong, Jibin Liu, Bin Li, Xiaoguang Li, Hui Wang.

   OBJECTIVE: The metabolic characteristics of liver cancer drive considerable hurdles to immune cells function and cancer immunotherapy. However, how metabolic reprograming in the tumour microenvironment impairs the antitumour immune response remains unclear.
DESIGN: Human samples and multiple murine models were employed to evaluate the correlation between GPR109A and liver cancer progression. GPR109A knockout mice, immune cells depletion and primary cell coculture models were used to determine the regulation of GPR109A on tumour microenvironment and identify the underlying mechanism responsible for the formation of intratumour GPR109A+myeloid cells.
RESULTS: We demonstrate that glutamine shortage in liver cancer tumour microenvironment drives an immunosuppressive GPR109A+myeloid cells infiltration, leading to the evasion of immune surveillance. Blockade of GPR109A decreases G-MDSCs and M2-like TAMs abundance to trigger the antitumour responses of CD8+ T cells and further improves the immunotherapy efficacy against liver cancer. Mechanistically, tumour cells and tumour-infiltrated myeloid cells compete for glutamine uptake via the transporter SLC1A5 to control antitumour immunity, which disrupts the endoplasmic reticulum (ER) homoeostasis and induces unfolded protein response of myeloid cells to promote GPR109A expression through IRE1α/XBP1 pathway. The restriction of glutamine uptake in liver cancer cells, as well as the blockade of IRE1α/XBP1 signalling or glutamine supplementation, can eliminate the immunosuppressive effects of GPR109A+ myeloid cells and slow down tumour progression.
CONCLUSION: Our findings identify the immunometabolic crosstalk between liver cancer cells and myeloid cells facilitates tumour progression via a glutamine metabolism/ER stress/GPR109A axis, suggesting that GPR109A can be exploited as an immunometabolic checkpoint and putative target for cancer treatment.

Keywords:  HEPATOCELLULAR CARCINOMA; IMMUNOLOGY IN HEPATOLOGY; IMMUNOTHERAPY

DOI:  https://doi.org/10.1136/gutjnl-2024-332429
Nat Commun. 2024 Jul 12. 15(1): 5857

Glucose-6-phosphate dehydrogenase maintains redox homeostasis and biosynthesis in LKB1-deficient KRAS-driven lung cancer.

Taijin Lan, Sara Arastu, Jarrick Lam, Hyungsin Kim, Wenping Wang, Samuel Wang, Vrushank Bhatt, Eduardo Cararo Lopes, Zhixian Hu, Michael Sun, Xuefei Luo, Jonathan M Ghergurovich, Xiaoyang Su, Joshua D Rabinowitz, Eileen White, Jessie Yanxiang Guo.

Cancer cells depend on nicotinamide adenine dinucleotide phosphate (NADPH) to combat oxidative stress and support reductive biosynthesis. One major NADPH production route is the oxidative pentose phosphate pathway (committed step: glucose-6-phosphate dehydrogenase, G6PD). Alternatives exist and can compensate in some tumors. Here, using genetically-engineered lung cancer mouse models, we show that G6PD ablation significantly suppresses KrasG12D/+;Lkb1-/- (KL) but not KrasG12D/+;P53-/- (KP) lung tumorigenesis. In vivo isotope tracing and metabolomics reveal that G6PD ablation significantly impairs NADPH generation, redox balance, and de novo lipogenesis in KL but not KP lung tumors. Mechanistically, in KL tumors, G6PD ablation activates p53, suppressing tumor growth. As tumors progress, G6PD-deficient KL tumors increase an alternative NADPH source from serine-driven one carbon metabolism, rendering associated tumor-derived cell lines sensitive to serine/glycine depletion. Thus, oncogenic driver mutations determine lung cancer dependence on G6PD, whose targeting is a potential therapeutic strategy for tumors harboring KRAS and LKB1 co-mutations.

DOI: https://doi.org/10.1038/s41467-024-50157-8
Biosci Rep. 2024 Jul 11. pii: BSR20240752. [Epub ahead of print]

Metabolic profiling and combined therapeutic strategies unveil the cytotoxic potential of selenium-chrysin (SeChry) in NSCLC cells.

Cindy Mendes, Isabel Lemos, Ana Hipólito, Bruna Abreu, Catarina Freitas-Dias, Filipa Martins, Rita Pires, Hélio Barros, Vasco Bonifácio, Luis Gonçalves, Jacinta Serpa.

  Lung cancer ranks as the predominant cause of cancer-related mortalities on a global scale. Despite progress in therapeutic interventions, encompassing surgical procedures, radiation, chemotherapy, targeted therapies and immunotherapy, the overall prognosis remains unfavorable. Imbalances in redox equilibrium and disrupted redox signaling, common traits in tumors, play crucial roles in malignant progression and treatment resistance. Cancer cells, often characterized by persistent high levels of reactive oxygen species (ROS) resulting from genetic, metabolic, and microenvironmental alterations, counterbalance this by enhancing their antioxidant capacity. Cysteine availability emerges as a critical factor in chemoresistance, shaping the survival dynamics of non‑small cell lung cancer (NSCLC) cells. Selenium-chrysin (SeChry) was disclosed as a modulator of cysteine intracellular availability. This study comprehensively characterizes the metabolism of SeChry and investigates its cytotoxic effects in NSCLC. SeChry treatment induces notable metabolic shifts, particularly in selenocompound metabolism, impacting crucial pathways such as glycolysis, gluconeogenesis, the tricarboxylic acid (TCA) cycle, and amino acid metabolism. Additionally, SeChry affects the levels of key metabolites such as acetate, lactate, glucose, and amino acids, contributing to disruptions in redox homeostasis and cellular biosynthesis. The combination of SeChry with other treatments, such as glycolysis inhibition and chemotherapy, results in greater efficacy. Furthermore, by exploiting NSCLC's capacity to consume lactate, the use of lactic acid-conjugated dendrimer nanoparticles for SeChry delivery is investigated, showing specificity to cancer cells expressing monocarboxylate transporters.

Keywords:  cancer metabolism; lung cancer; metabolic remodeling; new therapies; selenio-chrysin

DOI:  https://doi.org/10.1042/BSR20240752
J Gastrointest Oncol. 2024 Jun 30. 15(3): 1002-1019

Unveiling the impact of glutathione (GSH) and p53 gene deletion on tumor cell metabolism by amino acid and proteomics analysis.

Hui Zhang, Jing Zhou, Lei Dong, Liyu Zhu, Yingjiang Ye.

   Background: Tumor cell inhibition is a pivotal focus in anti-cancer research, and extensive investigations have been conducted regarding the role of p53. Numerous studies have highlighted its close association with reactive oxygen species (ROS). However, the precise impact of the antioxidant glutathione (GSH) in this context remains inadequately elucidated. Here, we will elucidate the anti-cancer mechanisms mediated by p53 following treatment with GSH.
Methods: In this study, we employed a p53 gene knockout approach in SW480 colorectal cells and conducted comprehensive analyses of 20 amino acids and proteomics using liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS).
Results: These analyses unveiled profound alterations in amino acids and proteins triggered by GSH treatment, shedding light on novel phenomena and delineating the intricate interplay between GSH and cellular proteins. The deletion of the p53 gene exerts a profound influence on tumor cell proliferation. Moreover, tumor cell proliferation is significantly affected by elevated GSH levels. Importantly, in the absence of the p53 gene, cells exhibit heightened sensitivity to GSH, leading to inhibited cell growth. The combined therapeutic approach involving GSH and p53 gene deletion expedites the demise of tumor cells. It is noteworthy that this treatment leads to a marked decline in amino acid metabolism, particularly affecting the down-regulation of methionine (Met) and phenylalanine (Phe) amino acids. Among the 41 proteins displaying significant changes, 8 exhibit consistent alterations, with 5 experiencing decreased levels and 3 demonstrating increased quantities. These proteins primarily participate in crucial cellular metabolic processes and immune functions.
Conclusions: In conclusion, the concurrent administration of GSH treatment and p53 gene deletion triggers substantial modifications in the amino acid and protein metabolism of tumor cells, primarily characterized by down-regulation. This, in turn, compromises cell metabolic activity and immune function, ultimately culminating in the demise of tumor cells. These newfound insights hold promising implications and could pave the way for the development of straightforward and efficacious anti-cancer treatments.

Keywords:  SW480; glutathione (GSH); methionine (Met); p53; proteomics

DOI:  https://doi.org/10.21037/jgo-24-236
Front Pharmacol. 2024 ;15 1423629

Metabolic reprogramming in esophageal squamous cell carcinoma.

Ziyi Wang, Xiangyu Sun, Zehui Li, Huidong Yu, Wenya Li, Yan Xu.

  Esophageal squamous cell carcinoma (ESCC) is a malignancy with high incidence in China. Due to the lack of effective molecular targets, the prognosis of ESCC patients is poor. It is urgent to explore the pathogenesis of ESCC to identify promising therapeutic targets. Metabolic reprogramming is an emerging hallmark of ESCC, providing a novel perspective for revealing the biological features of ESCC. In the hypoxic and nutrient-limited tumor microenvironment, ESCC cells have to reprogram their metabolic phenotypes to fulfill the demands of bioenergetics, biosynthesis and redox homostasis of ESCC cells. In this review, we summarized the metabolic reprogramming of ESCC cells that involves glucose metabolism, lipid metabolism, and amino acid metabolism and explore how reprogrammed metabolism provokes novel opportunities for biomarkers and potential therapeutic targets of ESCC.

Keywords:  amino acid; esophageal cancer; fatty acid; glucose; metabolic reprogramming

DOI:  https://doi.org/10.3389/fphar.2024.1423629
Sci Rep. 2024 Jul 11. 14(1): 16059

Curcumin synergistically enhances the efficacy of gemcitabine against gemcitabine-resistant cholangiocarcinoma via the targeting LAT2/glutamine pathway.

Phonpilas Thongpon, Kitti Intuyod, Sasitorn Chomwong, Thatsanapong Pongking, Sirinapha Klungsaeng, Kanha Muisuk, Naruechar Charoenram, Chutima Sitthirach, Raynoo Thanan, Porntip Pinlaor, Somchai Pinlaor.

  Cholangiocarcinoma (CCA) is often diagnosed late, leading to incomplete tumor removal, drug resistance and reduced chemotherapy efficacy. Curcumin has the potential for anti-cancer activity through various therapeutic properties and can improve the efficacy of chemotherapy. We aimed to investigate the synergistic effect of a combination of curcumin and gemcitabine against CCA, targeting the LAT2/glutamine pathway. This combination synergistically suppressed proliferation in gemcitabine-resistant CCA cells (KKU-213BGemR). It also resulted in a remarkable degree of CCA cell apoptosis and cell cycle arrest, characterized by a high proportion of cells in the S and G2/M phases. Knockdown of SLC7A8 decreased the expressions of glutaminase and glutamine synthetase, resulting in inhibited cell proliferation and sensitized CCA cells to gemcitabine treatment. Moreover, in vivo experiments showed that a combination curcumin and gemcitabine significantly reduced tumor size, tumor growth rate and LAT2 expression in a gemcitabine-resistant CCA xenograft mouse model. Suppression of tumor progression in an orthotopic CCA hamster model provided strong support for clinical application. In conclusion, curcumin synergistically enhances gemcitabine efficacy against gemcitabine-resistant CCA by induction of apoptosis, partly via inhibiting LAT2/glutamine pathway. This approach may be an alternative strategy for the treatment of gemcitabine-resistant in CCA patients.

Keywords:   SLC7A8 (LAT2); Cholangiocarcinoma; Curcumin; Drug resistance; Gemcitabine; Glutamine

DOI:  https://doi.org/10.1038/s41598-024-66945-7
Biochem Biophys Res Commun. 2024 Jul 06. pii: S0006-291X(24)00903-3. [Epub ahead of print]730 150367

CD39 is induced by nutrient deprivation in colorectal cancer cells and contributes to the tolerance to hypoxia.

Zhaochen Ning, Keyan Liu, Huabao Xiong.

  Rapid tumor growth and insufficient blood supply leads to the development of a hypoxic and nutrient deprived microenvironment. To survive, tumor cells need to tolerate these adverse conditions. Here we found the expression of CD39 was enhanced in necrotic regions distant from blood vessels. We speculate that this is a strategy for tumor cells to actively adapt to the hostile environment. Further studies showed that CD39 was induced by nutrient deprivation through the AMPK signalling pathway. We next explored the significance of CD39 for tumor cells. Our results showed that CD39 reduced cellular oxygen consumption, which could be significant for tumor cells if the available oxygen is limited. Metabolomics analysis showed that overexpression of CD39 significantly altered cellular metabolism, and tricarboxylic acid (TCA) cycle was identified as the most impacted metabolic pathway. In order to explore the molecular mechanism, we performed RNA-seq analysis. The results showed that CD39 significantly up-regulated the expression of pyruvate dehydrogenase kinase isozyme 2 (PDK2), thus inhibiting the activity of pyruvate dehydrogenase (PDH) and TCA cycle. Finally, CD39 was shown to protect tumor cells from hypoxia-induced cell death and reduce intratumoral hypoxia levels. CD39 has attracted a great deal of attention as a newly discovered immune checkpoint molecule in recent years. Our results indicate that CD39 not only plays a role in immune regulation, but also enables tumor cells to tolerate hypoxia by inhibiting TCA cycle and reducing cellular oxygen consumption. This study provides evidence that targeting CD39 may be a novel strategy to prevent adaptation of tumor cells in stressed conditions.

Keywords:  CD39; Hypoxia; Nutrient deprivation; Tumor microenvironment

DOI:  https://doi.org/10.1016/j.bbrc.2024.150367
Cancers (Basel). 2024 Jun 22. pii: 2302. [Epub ahead of print]16(13):

Pan-Cancer, Genome-Scale Metabolic Network Analysis of over 10,000 Patients Elucidates Relationship between Metabolism and Survival.

Jesse Bucksot, Katherine Ritchie, Matthew Biancalana, John A Cole, Daniel Cook.

  Despite the high variability in cancer biology, cancers nevertheless exhibit cohesive hallmarks across multiple cancer types, notably dysregulated metabolism. Metabolism plays a central role in cancer biology, and shifts in metabolic pathways have been linked to tumor aggressiveness and likelihood of response to therapy. We therefore sought to interrogate metabolism across cancer types and understand how intrinsic modes of metabolism vary within and across indications and how they relate to patient prognosis. We used context specific genome-scale metabolic modeling to simulate metabolism across 10,915 patients from 34 cancer types from The Cancer Genome Atlas and the MMRF-COMMPASS study. We found that cancer metabolism clustered into modes characterized by differential glycolysis, oxidative phosphorylation, and growth rate. We also found that the simulated activities of metabolic pathways are intrinsically prognostic across cancer types, especially tumor growth rate, fatty acid biosynthesis, folate metabolism, oxidative phosphorylation, steroid metabolism, and glutathione metabolism. This work shows the prognostic power of individual patient metabolic modeling across multiple cancer types. Additionally, it shows that analyzing large-scale models of cancer metabolism with survival information provides unique insights into underlying relationships across cancer types and suggests how therapies designed for one cancer type may be repurposed for use in others.

Keywords:  metabolic modeling; pan-cancer; prognosis; systems biology; therapy repurposing

DOI:  https://doi.org/10.3390/cancers16132302
Adv Sci (Weinh). 2024 Jul 12. e2401748

Overcoming Cancer Persister Cells by Stabilizing the ATF4 Promoter G-quadruplex.

Chengmei Xiao, Yipu Li, Yushuang Liu, Ruifang Dong, Xiaoyu He, Qing Lin, Xin Zang, Kaibo Wang, Yuanzheng Xia, Lingyi Kong.

  Persister cells (PS) selected for anticancer therapy have been recognized as a significant contributor to the development of treatment-resistant malignancies. It is found that imposing glutamine restriction induces the generation of PS, which paradoxically bestows heightened resistance to glutamine restriction treatment by activating the integrated stress response and initiating the general control nonderepressible 2-activating transcription factor 4-alanine, serine, cysteine-preferring transporter 2 (GCN2-ATF4-ASCT2) axis. Central to this phenomenon is the stress-induced ATF4 translational reprogramming. Unfortunately, directly targeting ATF4 protein has proven to be a formidable challenge because of its flat surface. Nonetheless, a G-quadruplex structure located within the promoter region of ATF4 (ATF4-G4) is uncovered and resolved, which functions as a transcriptional regulator and can be targeted by small molecules. The investigation identifies the natural compound coptisine (COP) as a potent binder that interacts with and stabilizes ATF4-G4. For the first time, the high-resolution structure of the COP-ATF4-G4 complex is determined. The formation of this stable complex disrupts the interaction between transcription factor AP-2 alpha (TFAP2A) and ATF4-G4, resulting in a substantial reduction in intracellular ATF4 levels and the eventual death of cancer cells. These seminal findings underscore the potential of targeting the ATF4-G4 structure to yield significant therapeutic advantages within the realm of persister cancer cells induced by glutamine-restricted therapy.

Keywords:  ATF4; G‐quadruplex; coptisine; glutamine‐restrictive therapy

DOI:  https://doi.org/10.1002/advs.202401748
PLoS Pathog. 2024 Jul 08. 20(7): e1011909

Norovirus NS1/2 protein increases glutaminolysis for efficient viral replication.

Adam Hafner, Noah Meurs, Ari Garner, Elaine Azar, Aditya Kannan, Karla D Passalacqua, Deepak Nagrath, Christiane E Wobus.

Viruses are obligate intracellular parasites that rely on host cell metabolism for successful replication. Thus, viruses rewire host cell pathways involved in central carbon metabolism to increase the availability of building blocks for successful propagation. However, the underlying mechanisms of virus-induced alterations to host metabolism are largely unknown. Noroviruses (NoVs) are highly prevalent pathogens that cause sporadic and epidemic viral gastroenteritis. In the present study, we uncovered several strain-specific and shared host cell metabolic requirements of three murine norovirus (MNV) strains, MNV-1, CR3, and CR6. While all three strains required glycolysis, glutaminolysis, and the pentose phosphate pathway for optimal infection of macrophages, only MNV-1 relied on host oxidative phosphorylation. Furthermore, the first metabolic flux analysis of NoV-infected cells revealed that both glycolysis and glutaminolysis are upregulated during MNV-1 infection of macrophages. Glutamine deprivation affected the viral lifecycle at the stage of genome replication, resulting in decreased non-structural and structural protein synthesis, viral assembly, and egress. Mechanistic studies further showed that MNV infection and overexpression of the non-structural protein NS1/2 increased the enzymatic activity of the rate-limiting enzyme glutaminase. In conclusion, the inaugural investigation of NoV-induced alterations to host glutaminolysis identified NS1/2 as the first viral molecule for RNA viruses that regulates glutaminolysis either directly or indirectly. This increases our fundamental understanding of virus-induced metabolic alterations and may lead to improvements in the cultivation of human NoVs.

DOI: https://doi.org/10.1371/journal.ppat.1011909
J Thorac Dis. 2024 Jun 30. 16(6): 3967-3989

A novel amino acid metabolism-related gene signature to predict the overall survival of esophageal squamous cell carcinoma patients.

Kebing Chen, Zhizhong Lin, Yongshi Shen, Yijin Lin, Juhui Chen, Guy D Eslick, Yuanmei Chen, Yuanji Xu, Yong Xin.

   Background: Esophageal squamous cell carcinoma (ESCC) has a poor early detection rate, prognosis, and survival rate. Effective prognostic markers are urgently needed to assist in the prediction of ESCC treatment outcomes. There is accumulating evidence of a strong relationship between cancer cell growth and amino acid metabolism. This study aims to determine the relationship between amino acid metabolism and ESCC prognosis.
Methods: This study comprehensively evaluates the association between amino acid metabolism-related gene (AAMRG) expression profiles and the prognosis of ESCC patients based on data from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO) databases. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to verify the expression of prognosis-related genes.
Results: A univariate Cox regression analysis of TCGA data identified 18 prognosis-related AAMRGs. The gene expression profiles of 90 ESCC tumor and normal tissues were obtained from the GSE20347 and GSE67269 datasets. Two differently expressed genes (DEGs) were considered as ESCC prognosis-related genes; and they were branched-chain amino acid transaminase 1 (BCAT1) and methylmalonic aciduria and homocystinuria type C protein (MMACHC). These two AAMRGs were used to develop a novel AAMRG-related gene signature to predict 1- and 2-year prognostic risk in ESCC patients. Both BCAT1 and MMACHC expression were verified by RT-qPCR. A prognostic nomogram that incorporated clinical factors and BCAT1 and MMACHC gene expression was constructed, and the calibration plots showed that it had good prognostic performance.
Conclusions: The AAMRG signature established in our study is efficient and could be used in clinical settings to predict the early prognosis of ESCC patients.

Keywords:  Amino acid metabolism-related gene (AAMRG); esophageal squamous cell carcinoma (ESCC); prediction model; prognosis nomogram; risk signature

DOI:  https://doi.org/10.21037/jtd-24-818
Adv Sci (Weinh). 2024 Jul 11. e2308032

Metabolic Profiling of Cochlear Organoids Identifies α-Ketoglutarate and NAD+ as Limiting Factors for Hair Cell Reprogramming.

Qing Liu, Linqing Zhang, Zhen Chen, Yihan He, Yuhang Huang, Cui Qiu, Chengwen Zhu, Danxia Zhou, Zhenji Gan, Xia Gao, Guoqiang Wan.

  Cochlear hair cells are the sensory cells responsible for transduction of acoustic signals. In mammals, damaged hair cells do not regenerate, resulting in permanent hearing loss. Reprogramming of the surrounding supporting cells to functional hair cells represent a novel strategy to hearing restoration. However, cellular processes governing the efficient and functional hair cell reprogramming are not completely understood. Employing the mouse cochlear organoid system, detailed metabolomic characterizations of the expanding and differentiating organoids are performed. It is found that hair cell differentiation is associated with increased mitochondrial electron transport chain (ETC) activity and reactive oxidative species generation. Transcriptome and metabolome analyses indicate reduced expression of oxidoreductases and tricyclic acid (TCA) cycle metabolites. The metabolic decoupling between ETC and TCA cycle limits the availability of the key metabolic cofactors, α-ketoglutarate (α-KG) and nicotinamide adenine dinucleotide (NAD+). Reduced expression of NAD+ in cochlear supporting cells by PGC1α deficiency further impairs hair cell reprogramming, while supplementation of α-KG and NAD+ promotes hair cell reprogramming both in vitro and in vivo. These findings reveal metabolic rewiring as a central cellular process during hair cell differentiation, and highlight the insufficiency of key metabolites as a metabolic barrier for efficient hair cell reprogramming.

Keywords:  NAD+; cochlear organoids; hair cells; reprogramming; α‐ketoglutarate

DOI:  https://doi.org/10.1002/advs.202308032
Nutrients. 2024 Jul 03. pii: 2126. [Epub ahead of print]16(13):

Usefulness of Perioperative Nutritional Therapy with the Glutamine/Arginine/Calcium β-Hydroxy-β-Methylbutyrate Product in Esophageal Cancer Surgery: A Single-Center Retrospective Study.

Koichi Okamoto, Hiroyuki Takamura, Taigo Nagayama, Yuta Sannomiya, Akifumi Hashimoto, Hisashi Nishiki, Daisuke Kaida, Takashi Miyata, Toshikatsu Tsuji, Hideto Fujita, Shinichi Kinami, Itasu Ninomiya, Noriyuki Inaki.

  A useful perioperative nutritional therapy for highly invasive esophageal cancer surgical cases needs to be developed. We clarified the usefulness of amino-acid-enriched nutritional therapy using glutamine (Gln)/arginine (Arg)/calcium β-hydroxy-β-methylbutyrate (HMB) products on the short-term postoperative outcomes of minimally invasive esophagectomy for esophageal cancer. Altogether, 114 patients (Gln/Arg/HMB group) received perioperative nutritional therapy with Gln/Arg/HMB products, and we retrospectively investigated the change in nutritional parameters including skeletal muscle mass, occurrence of postoperative complications, and short-term postoperative outcomes in this group. The results were compared between the Gln/Arg/HMB and control groups (79 patients not receiving the Gln/Arg/HMB products). The incidence of all postoperative complications, sputum expectoration disorder, and pleural effusion of grade ≥ III was significantly lower in the Gln/Arg/HMB group (62.0% vs. 38.6%, p = 0.001; 44.3% vs. 28.1%, p = 0.020; 27.8% vs. 13.2%, p = 0.011, respectively). The psoas muscle area and postoperative body weight were significantly higher at 1 month and 1 year after surgery in the Gln/Arg/HMB group than in the control group (93.5% vs. 99.9%, p < 0.001; 92.0% vs. 95.4%, p = 0.006). Perioperative amino-acid-enriched nutritional therapy may improve the short-term postoperative outcomes, nutritional status, and skeletal muscle mass of esophageal cancer surgical patients.

Keywords:  complication; esophageal cancer; minimally invasive esophagectomy; sarcopenia

DOI:  https://doi.org/10.3390/nu16132126