bims-glucam 2025-07-27 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–07–27
ten papers selected by
Sreeparna Banerjee, Middle East Technical University

c-Myc promotes metabolic reprogramming in pulmonary hypertension via the stimulation of glutaminolysis and the reductive tricarboxylic acid cycle.
Nymphoides peltata Alleviates Patulin-Induced Glutamine Metabolic Stress and Epithelial Toxicity in Small Intestinal Epithelial Cells.
Activation of the integrated stress response and loss of cFLIPL under glutamine limitation induce IL-8 gene expression and secretion in glutamine-dependent tumor cells.
mTORC1 senses glutamine and other amino acids through GCN2.
Disruption of glutamine transport uncouples the NUPR1 stress-adaptation program and induces prostate cancer radiosensitivity.
The Negative Feedback of the Glutamine/Prostatitis Loop Identified Among 1400 Metabolites and Prostatitis via Mendelian Randomization.
The metabolic significance of ATP-citrate lyase in cancer: insights into glutamine-fuelled citrate biosynthesis and tumour progression.
Predicting hepatocellular carcinoma development in advanced fibrosis or cirrhosis due to chronic hepatitis B: The role of glypican-3, heat shock protein 70, CD34, and glutamine synthetase.
Glutaminase as a metabolic target of choice to counter acquired resistance to Palbociclib by colorectal cancer cells.
D-glucaro-1,4-lactone alleviates acetaminophen-induced hepatotoxicity in mice via modulating gut microbiota and metabolites associated with Lactobacillus-glutamine and nicotinic acid pathways.

Redox Biol. 2025 Jul 09. pii: S2213-2317(25)00278-2. [Epub ahead of print]85 103765

c-Myc promotes metabolic reprogramming in pulmonary hypertension via the stimulation of glutaminolysis and the reductive tricarboxylic acid cycle.

Manivannan Yegambaram, Xutong Sun, Qing Lu, Alejandro Garcia Flores, Marina Zemskova, Jamie Soto, Adam Rauckhorst, Emin Maltepe, Ting Wang, Jeffrey R Fineman, Stephen M Black.

  Endothelial cell (EC) dysfunction is key in initiating and progressing pulmonary hypertension (PH). EC dysfunction in PH leads to hyperproliferation and vascular remodeling of the pulmonary blood vessels. Increased glutaminolysis and altered cellular metabolism are pivotal in hyperproliferative cancer cells. However, whether a similar enhancement in glutamine metabolism is involved in the EC hyperproliferation and if this contributes to vascular remodeling during PH development is unresolved and was the focus of our study. Metabolic flux analysis showed elevated glutaminolysis and enhanced metabolic flux through the reductive tricarboxylic acid (TCA) cycle in pulmonary arterial ECs isolated from an ovine experimental model of PH (PH-PAECs). PH-PAECs also exhibited increased c-Myc protein levels, a master regulator of glutaminolysis. Therefore, we assessed the effect of increased c-Myc expression on metabolic reprogramming, glutaminolysis, and proliferation in control PAECs. Results from a comprehensive snapshot metabolomics investigation and metabolic flux analysis confirmed the reprogramming of mitochondrial metabolism, enhanced glutamine metabolism, and increased glycolysis in c-Myc overexpressing PAECs. Additionally, c-Myc overexpression impacted the ATP production rate, disrupted mitochondrial respiration, increased reactive oxygen species production, induced cell proliferation, and suppressed apoptosis. Functionally, these metabolic changes suppressed nitric oxide (NO) production. We also demonstrate that a small-molecule c-Myc inhibitor, 10058-F4, attenuates glutaminolysis, suppresses the reverse TCA cycle and glycolysis, and reverses the hyperproliferative phenotype, thereby restoring NO levels in PH-PAECs. We also demonstrate that directly targeting HIF-1α reverses the hyper-proliferative, anti-apoptotic phenotype in PH-PAECs. Thus, targeting c-Myc signaling and suppressing glutaminolysis or glycolysis could be a novel therapy for PH.

Keywords:  Endothelial cells; Glutaminolysis; Glycolysis; Metabolomics; Proliferation; Pulmonary hypertension

DOI:  https://doi.org/10.1016/j.redox.2025.103765
Toxins (Basel). 2025 Jul 03. pii: 337. [Epub ahead of print]17(7):

Nymphoides peltata Alleviates Patulin-Induced Glutamine Metabolic Stress and Epithelial Toxicity in Small Intestinal Epithelial Cells.

Chae Hyun Lee, Sangsu Shin, Tae Hyun Kim, Sang In Lee.

  Patulin (PAT) is a mycotoxin commonly found in fruits and contaminated feedstuffs, known for its gastrointestinal and systemic toxicity. However, the mechanisms underlying PAT-induced damage to intestinal epithelial cells remain poorly understood. In this study, we demonstrated that 6.5 µM PAT exposure for 24 h reduced glutamine (GLN) uptake and altered the expression of GLN transporters and related metabolic enzymes in IPEC-J2 cells. This concentration was selected based on previous in vitro studies that reported PAT-induced cytotoxicity in porcine intestinal epithelial cells. Moreover, PAT also upregulated ER stress markers (DDIT3, EIF2AK3, ERN1, and HSPA5) and inflammatory cytokines (IL-8, IL-1β, and TNF-α), while decreasing ZO-1 localization, indicating disrupted epithelial barrier integrity. Although 6 mM GLN supplementation only partially mediated ER stress and inflammatory responses, it more effectively restored ZO-1 localization. A high-throughput screening of 324 natural products was conducted to identify potential protective agents, identifying Nymphoides peltata extract as a promising candidate. Co-treatment with 80 ng/μL N. peltata extract improved GLN uptake, partially alleviated ER stress and inflammation, and significantly restored tight junction structure in PAT-exposed cells. Collectively, these findings suggest that N. peltata could serve as a novel natural therapeutic for enhancing intestinal resilience against PAT-induced toxicity. Specifically, this study highlights the potential use of N. peltata extract as a natural feed additive to protect intestinal health in livestock under mycotoxin stress.

Keywords:  ER stress; Nymphoides peltata; glutamine metabolism; inflammation; intestinal epithelial barrier; natural products; patulin

DOI:  https://doi.org/10.3390/toxins17070337
Cell Death Discov. 2025 Jul 19. 11(1): 332

Activation of the integrated stress response and loss of cFLIPL under glutamine limitation induce IL-8 gene expression and secretion in glutamine-dependent tumor cells.

Rocío Mora-Molina, F Javier Fernández-Farrán, Abelardo López-Rivas, Carmen Palacios.

Growing evidence suggests that the proapoptotic TNF-related apoptosis-inducing ligand receptor 2 (TRAIL-R2/DR5) signaling pathway can also trigger the production of inflammatory cytokines, thereby promoting tumor progression. We recently reported that glutamine depletion impacts the survival of glutamine-dependent tumor cells by activating the TRAIL-R2/DR5-mediated apoptotic machinery. However, it remains unclear whether glutamine limitation activates a TRAIL-R2/DR5-regulated inflammatory response. In this study, we demonstrate that glutamine starvation activates two parallel signaling pathways, leading to the gene expression and secretion of the pro-angiogenic and pro-inflammatory interleukin-8 (IL-8/CXCL8) in tumor cells. Our findings reveal that the amino acid-sensing general control nonderepressible-2 kinase (GCN2)/activating transcription factor 4 (ATF4) signaling axis contributes to the upregulation of IL-8 gene expression in glutamine-deprived tumor cells. Furthermore, our results indicate that the loss of the long isoform of cellular FLICE-inhibitory protein (cFLIPL), which occurs as result of the metabolic stress induced by glutamine limitation, promotes TRAIL-independent activation of the NF-kB pathway via TRAIL-R2/DR5, a key mechanism driving the observed IL-8 upregulation under starvation conditions. Given the severe depletion of glutamine observed in growing tumors, our data suggest that IL-8 secretion, induced by this metabolic stress, may play a significant role in activating inflammatory and angiogenic responses, thereby counteracting apoptosis and ultimately promoting tumor progression.

DOI: https://doi.org/10.1038/s41420-025-02625-3
EMBO J. 2025 Jul 21.

mTORC1 senses glutamine and other amino acids through GCN2.

Gianluca Figlia, Sandra Müller, Fabiola Garcia-Cortizo, Marilena Neff, Glynis Klinke, Gernot Poschet, Aurelio A Teleman.

  mTORC1 promotes cell growth when nutrients such as amino acids are available. While dedicated sensors relaying availability of leucine, arginine and methionine to mTORC1 have been identified, it is still unclear how mTORC1 senses glutamine, one of its most potent inducers. Here, we find that glutamine is entirely sensed through the protein kinase GCN2, whose initial activation is not triggered by depletion of glutamine itself, but by the concomitant depletion of asparagine. In turn, GCN2 leads to a succession of events that additively inhibit mTORC1: within 1 h, GCN2 inhibits mTORC1 through the Rag GTPases, independently of its function as an eIF2α kinase. Later, GCN2-mediated induction of ATF4 upregulates Ddit4 followed by Sestrin2, which together cause additional mTORC1 inhibition. Additionally, we find that depletion of virtually any other amino acid also inhibits mTORC1 through GCN2. GCN2 and the dedicated amino acid sensors thus represent two independent systems that enable mTORC1 to perceive a wide spectrum of amino acids.

Keywords:  Amino Acid Sensors; Asparagine; GCN2; Glutamine; mTORC1

DOI:  https://doi.org/10.1038/s44318-025-00505-1
Cell Commun Signal. 2025 Jul 24. 23(1): 351

Disruption of glutamine transport uncouples the NUPR1 stress-adaptation program and induces prostate cancer radiosensitivity.

Uğur Kahya, Vasyl Lukiyanchuk, Ielizaveta Gorodetska, Matthias M Weigel, Ayşe Sedef Köseer, Berke Alkan, Dragana Savic, Annett Linge, Steffen Löck, Mirko Peitzsch, Ira-Ida Skvortsova, Mechthild Krause, Anna Dubrovska.

   BACKGROUND: Metabolic and stress response adaptations in prostate cancer (PCa) mediate tumor resistance to radiation therapy (RT). Our study investigated the roles of glutamine (Gln) transporters SLC1A5, SLC7A5, and SLC38A1 in regulating NUPR1-mediated stress response, PCa cell survival, metabolic reprogramming, and response to RT.
METHODS: The radiosensitizing potential of GLS inhibition with CB-839 was analyzed in prostate cancer xenograft models. The level of gene expression was analyzed by RNA sequencing and RT-qPCR in the established cell lines or patient-derived tumor and adjacent non-cancerous tissues. Phosphoproteomic analysis was employed to identify the underlying signaling pathways. The publicly available PCa patient datasets, and a dataset for the patients treated with RT were analyzed by SUMO software. The key parameters of mitochondrial functions were measured by Seahorse analysis. Analysis of the general oxidative stress level and mitochondrial superoxide detection were conducted using flow cytometry. γH2A.X foci analysis was used to assess the DNA double strand break. Relative cell sensitivity to RT was evaluated by radiobiological clonogenic assays. Aldefluor assay and sphere-forming analysis were used to determine cancer stem cell (CSC) phenotype.
RESULTS: A siRNA-mediated knockdown of Gln transporters SLC1A5, SLC7A5, and SLC38A1 resulted in significant radiosensitization of PCa cells. Consistently, the first-in-clinic glutaminase (GLS) inhibitor CB-839, combined with RT, demonstrated a synergistic effect with radiotherapy in vivo, significantly delaying tumor growth. Inhibition of Gln metabolism or knockdown of Gln transporters SLC1A5, SLC7A5, or SLC38A1 induces expression of NUPR1, a stress response transcriptional regulator, but simultaneously uncouples the NUPR1-driven metabolic stress-adaptation program. Similarly to the effect from NUPR1 knockdown, depletion of these Gln transporters led to reduced cell viability, accumulation of mitochondrial ROS, and increased PCa radiosensitivity. This effect is more pronounced in PCa cells with high dependency on OXPHOS for energy production.
CONCLUSIONS: Our work underscores the role of Gln transporters and the NUPR1-mediated stress response in PCa cell survival, oxidative stress, mitochondrial functions, and radioresistance. Our findings provide a potential therapeutic in vivo strategy to enhance the efficacy of RT and suggest a potential synergism between the depletion of Gln transporters or NUPR1 and OXPHOS inhibition.

Keywords:  GLS; Glutamine transporters; Mitochondria; NUPR1; Oxidative stress; Prostate cancer; Radiation

DOI:  https://doi.org/10.1186/s12964-025-02344-3
Mediators Inflamm. 2025 ;2025 9648279

The Negative Feedback of the Glutamine/Prostatitis Loop Identified Among 1400 Metabolites and Prostatitis via Mendelian Randomization.

Yi Wang, Hao Ji, Yingfei Chen, Bingye Zhu, Yongming Peng, Qianwei Xing.

  Background: Prostatitis remains a clinically tricky problem due to its enigmatic etiologies, low cure rates, and relatively high recurrence rates. Therefore, we first employed Mendelian randomization to disclose the causal relationships among 1400 metabolites and prostatitis for a better understanding of the etiologies of prostatitis and thus identifying effective therapeutic targets. Methods: Prostatitis or metabolite-related data were derived from the online FinnGen or genome-wide association study (GWAS) Catalog datasets. Two-sample Mendelian randomization was employed, and sensitivity analyses, including heterogeneity, pleiotropy, and leave-one-out analysis, were applied to evaluate its stability. Results: Four potentially metabolic etiologies were identified for prostatitis, including glutamine degradant levels, adenosine 5'-monophosphate (AMP)-inosine 5'-monophosphate (IMP) ratio, glycolithocholate-glycolithocholate sulfate ratio, and AMP-citrate ratio. Therein, genetic susceptibility to the glutamine degradant levels, the AMP-IMP ratio, or the glycolithocholate-glycolithocholate sulfate ratio could decrease, while the AMP to citrate ratio might increase the risks of prostatitis. Moreover, two potential metabolic phenotypes of prostatitis were also identified, containing glutamine degradant levels and histidine betaine (hercynine) levels, indicating that genetic susceptibility to prostatitis could increase the risks of these two metabolites. Interestingly, we unexpectedly identified the negative feedback of the glutamine/prostatitis loop, showing that not only genetic susceptibility to glutamine degradant levels could decrease the risks of prostatitis but also genetic susceptibility to prostatitis could increase the risks of glutamine degradant levels. Conclusion: Four metabolic etiologies, two metabolic phenotypes, and the glutamine/prostatitis negative feedback loop were first identified by us for prostatitis in the European population to better understand its etiologies and offer novel treatment targets.

Keywords:  Mendelian randomization; clinical implications; metabolites; negative feedback loop; prostatitis

DOI:  https://doi.org/10.1155/mi/9648279
Med Oncol. 2025 Jul 19. 42(8): 349

The metabolic significance of ATP-citrate lyase in cancer: insights into glutamine-fuelled citrate biosynthesis and tumour progression.

Mohammed Bader, Omar Galy, Mohamed Babiker, Loai Eletr, Mustafa Saeed, Obai Suliman, Muzamil Mahdi Abdel Hamid.

  ATP-citrate lyase (ACLY) is a major metabolic enzyme involved in the citrate to acetyl-CoA conversion, connecting glycolysis with lipid biosynthesis. More evidence has been given for its cancer metabolic role, but its patterns of expression and prognostic value in various cancers remain unclear, particularly in the process of cancer metabolic reprogramming, a feature of cancer progression and drug resistance. We performed a pan-cancer analysis of ACLY expression in six tumour types, bladder urothelial carcinoma (BLCA), breast invasive carcinoma (BRCA), kidney chromophobe (KICH), kidney renal clear cell carcinoma (KIRC), kidney renal papillary cell carcinoma (KIRP), and liver hepatocellular carcinoma (LIHC), using public databases like TIMER, GEPIA, UALCAN, and cBioPortal. GEPIA and UALCAN were utilized for evaluating prognostic significance, and GEO datasets for external validation. ACLY was consistently overexpressed in reprogrammed cancers (BLCA, BRCA, KIRC, KIRP, and LIHC) (P < 0.05 to P < 0.001) but appreciably downregulated in KICH, a metabolically quiescent cancer. ACLY overexpression was associated with poor prognosis in LIHC and KICH (P = 0.011 and P = 0.0081, respectively) but surprisingly associated with better survival in KIRC (P < 0.0001). Genomic alterations in ACLY were rare (< 4%) across all cancers. The findings were validated by multiple GEO datasets: GSE41804 (LIHC), GSE 3167 (BLCA), GSE 22820 (BRCA), GSE 53757 (KIRC), GSE15641 (KIRP), and GSE15641 (KICH). Conclusion: ACLY expression agrees with the metabolic phenotype of most tumours and has different prognostic implications. Overexpression in metabolically active cancers and association with poor outcomes, namely in LIHC, emphasizes its potential for therapeutic targeting as a tumour metabolic status biomarker. Downregulation in KICH, on the other hand, agrees with evidence of metabolic stability in certain cancers. These findings might be used in the direction of metabolism-based therapeutic approaches and risk stratification in oncology.

Keywords:  ATP-citrate lyase (ACLY); Cancer metabolism; Metabolic reprogramming

DOI:  https://doi.org/10.1007/s12032-025-02909-9
Hepatol Forum. 2025 ;6(3): 99-104

Predicting hepatocellular carcinoma development in advanced fibrosis or cirrhosis due to chronic hepatitis B: The role of glypican-3, heat shock protein 70, CD34, and glutamine synthetase.

Yusuf Ozturk, Tugrul Purnak, Halis Simsek, Cenk Sokmensuer.

   Background and Aim: Numerous studies have demonstrated associations between hepatocellular carcinoma (HCC)-related features and markers such as glypican-3 (GPC3), heat shock protein 70 (HSP70), CD34, and glutamine synthetase (GS). In this study, we aimed to quantify these markers in the tissues of patients with cirrhosis or advanced fibrosis due to chronic hepatitis B (CHB).
Materials and Methods: A retrospective review was conducted on patients with CHB who developed pathologically confirmed HCC and underwent surgical resection between 2003 and 2013. A total of 24 patients who had paired malignant and surrounding cirrhotic tissue samples were included. Liver tissues were categorized as pre-HCC cirrhotic tissue, peritumoral cirrhotic tissue, and malignant HCC tissue. Non-cirrhotic liver samples from CHB patients served as controls.
Results: GPC3 staining was observed to be strong in 80% of HCC tissues and was positive in 70% of cirrhotic tissue surrounding HCC. In cirrhotic tissue 44 months prior to HCC development, 60% of cases were GPC3 positive. In non-cirrhotic chronic viral hepatitis, 20% of cases were GPC3 positive. GPC3, CD34, and GS showed significantly stronger staining in malignant versus control tissue (p<0.05). CD34 showed the highest discriminatory performance for malignant versus cirrhotic tissue (sensitivity=91.7%, specificity=91.7%), while GPC3 had the highest sensitivity (83.4%) in differentiating malignant from non-cirrhotic tissue.
Conclusion: GPC3 expression may be a predictive marker for HCC development in patients with CHB-related cirrhosis. CD34 also has considerable accuracy in differentiating HCC from cirrhotic and non-cirrhotic tissues, supporting a role for use in HCC detection.

Keywords:  CD34; Glypican-3; chronic hepatitis B; cirrhosis; hepatocellular carcinoma; predictive markers

DOI:  https://doi.org/10.14744/hf.2025.2025.0002
Oncogene. 2025 Jul 22.

Glutaminase as a metabolic target of choice to counter acquired resistance to Palbociclib by colorectal cancer cells.

Míriam Tarrado-Castellarnau, Carles Foguet, Josep Tarragó-Celada, Marc Palobart, Claudia Hernández-Carro, Jordi Perarnau, Erika Zodda, Ibrahim H Polat, Silvia Marin, Alejandro Suarez-Bonnet, Juan José Lozano, Mariia Yuneva, Timothy M Thomson, Marta Cascante.

Several mechanisms of resistance of cancer cells to cyclin-dependent kinase inhibitors (CDKi) have been identified, including the upregulation of metabolic regulators such as glutaminase. However, whether such resistance mechanisms represent optimal targets has not been determined. Here, we have systematically analyzed metabolic reprogramming in colorectal cancer cells exposed to Palbociclib, a CDKi selectively targeting CDK4/6, or Telaglenastat, a selective glutaminase inhibitor. Through multiple approaches, we show that Palbociclib and Telaglenastat elicit complementary metabolic responses and are thus uniquely suited to counter the metabolic reprogramming induced by the reciprocal drug. As such, while Palbociclib induced reduced tumor growth in vivo, and Telaglenastat did not show a significant effect, the drug combination displayed a strong synergistic effect on tumor growth. Likewise, initial responses to Palbociclib were followed by signs of adaptation and resistance, which were prevented by combining Palbociclib with Telaglenastat. In conclusion, combination with Telaglenastat optimally forestalls acquired resistance to Palbociclib in cancer cells.

DOI: https://doi.org/10.1038/s41388-025-03495-w
Front Pharmacol. 2025 ;16 1627850

D-glucaro-1,4-lactone alleviates acetaminophen-induced hepatotoxicity in mice via modulating gut microbiota and metabolites associated with Lactobacillus-glutamine and nicotinic acid pathways.

Zhiying Song, Yiran Pan, Zeyu Wang, Yujing Chen, Yufeng Deng, Lele Wang, Qi Hu, Wenxiang Huang, Shuilin Sun, Baogang Xie.

   Objective: This study investigated the hepatoprotective effect and underlying mechanisms of D-glucaro-1,4-lactone (1,4-GL), a natural compound found in fruits and vegetables, against acetaminophen (APAP)-induced acute liver injury (ALI) in mice, which had not been previously explored.
Methods: A stable ALI model was established in male C57BL/6J mice using 300 mg/kg APAP after fasting. Mice were pretreated orally with glutathione (200 mg/kg), or 1,4-GL (100 mg/kg or 200 mg/kg) for five consecutive days before APAP challenge. Serum biochemical markers were measured. Liver histopathology was assessed via H&E staining. Gut microbiota composition was analyzed using 16S rRNA sequencing of fecal samples. Liver metabolites were profiled using 1HNMR metabolomics.
Results: 1,4-GL pretreatment (especially 200 mg/kg) significantly ameliorated APAP-induced liver damage: it reduced serum ALT, AST, TBIL, and MDA levels (P < 0.05), increased GSH and SOD levels (P < 0.05), and attenuated hepatic necrosis and inflammation. 1,4-GL increased the abundance of the beneficial gut bacterium Lactobacillus (significantly reduced by APAP) and elevated hepatic levels of protective metabolites isoleucine, glutamine, and nicotinic acid. Correlation analyses between gut microbiota and liver metabolites revealed that glutamine and nicotinic acid were significantly positively correlated with Firmicutes and Lactobacillus, while showing a significant negative correlation with Lachnoclostridium. Lactobacillus was identified as a key beneficial bacterium, whereas Lachnoclostridium was associated with increased disease severity.
Conclusion: 1,4-GL exerts a beneficial regulatory effect on APAP-induced ALI by the Lactobacillus-glutamine/nicotinic acid pathway, highlighting its potential as a therapeutic agent for drug-induced liver injury.

Keywords:  D-glucaro-1,4-lactone; Lactobacillus; acetaminophen; acute liver injury; glutamine; nicotinic acid

DOI:  https://doi.org/10.3389/fphar.2025.1627850