bims-glucam 2025-08-17 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2025–08–17
ten papers selected by
Sreeparna Banerjee, Middle East Technical University

Real-Time Tracking of ASCT2-Mediated Glutamine Uptake in Living Tumors With a Bioorthogonal Bioluminescent Probe.
Repurposing Asparaginase Therapy to Target Cisplatin-Resistant Cancer Cells.
Clinical and biological impact of SNAT7 in lung adenocarcinoma: implications for prognosis and treatment.
Ketone body, as an emerging modulator of metabolic reprogramming and epigenetics in breast cancer.
Hypoxia-induced PYCR1 regulates glycolysis and histone lactylation to promote bladder cancer progression and metastasis via SLC6A14/Glutamine metabolism.
Restricting metabolic plasticity enhances stress adaptation through the modulation of PDH and HIF1A in TRAP1-depleted colon cancer.
Androgens drive SLC1A5-dependent metabolic reprogramming in polycystic ovary syndrome.
Molecular Mechanisms and Clinical Implications of Complex Prehabilitation in Colorectal Cancer Surgery: A Comprehensive Review.
MiR-195-5p regulates oxidative stress and aerobic metabolism by directly downregulating GLS2 in high glucose-induced human lens epithelial cells.
Modeling uncertainty: the impact of noise in T cell differentiation.

Adv Sci (Weinh). 2025 Aug 10. e07057

Real-Time Tracking of ASCT2-Mediated Glutamine Uptake in Living Tumors With a Bioorthogonal Bioluminescent Probe.

Bing-Jun Zhou, Ji-Lei Zhao, Fan Yin, Wen-Da Chen, Yi Sun, Ying-Ying Ren, Yi-Min Chen, Tian Xie, Chong Duan, Jian-Liang Zhou.

  Glutamine addiction, as a hallmark of tumor metabolism, drives malignant progression via proliferation, survival, and metastasis. Alanine-serine-cysteine transporter 2 (ASCT2), the primary glutamine transporter, is overexpressed in tumors to meet metabolic demands, making it a promising therapeutic target. Accurately monitoring ASCT2-mediated glutamine uptake is essential for investigating tumor metabolism and developing ASCT2-targeted therapeutics. However, current methods lack specificity, require laborious sample processing, and do not support real-time measurements in living systems. To overcome these issues, BLGLN is designed, an innovative bioluminescent reporter system exploiting Staudinger ligation. BLGLN comprises two components: 1) BL568, a caged D-luciferin derivative protected with 2-diphenylphosphinobenzoic acid, and 2) AA201, an azide-modified glutamine mimetic taken up by ASCT2. Once inside, AA201 undergoes Staudinger ligation with membrane-permeable BL568, releasing D-luciferin that is converted by luciferase into a bioluminescent signal, allowing real-time tracking of ASCT2-dependent glutamine uptake in tumors. BLGLN provides simplified synthesis, eliminates complex sample preparation, and enables real-time tracking and evaluation of glutamine uptake rate in living tumors.

Keywords:  ASCT2; bioluminescent probe; glutamine uptake; real‐time monitoring

DOI:  https://doi.org/10.1002/advs.202507057
Fundam Clin Pharmacol. 2025 Oct;39(5): e70044

Repurposing Asparaginase Therapy to Target Cisplatin-Resistant Cancer Cells.

Jiantao Wang, Nasim Pouryaghoub, Robert Strauss, Jiri Bartek, Si Min Zhang, Sean G Rudd.

   BACKGROUND: Cisplatin and its derivatives remain a cornerstone in the treatment of solid malignancies. Resistance is a major factor limiting their clinical utility.
OBJECTIVES: In the present study, we set out to interrogate therapeutic approaches to target cisplatin-resistant cancer cells. We focused on therapies exploiting metabolic pathways that are altered in drug-resistant cells. We sought to find an existing therapy that has monotherapy efficacy against cisplatin-resistant cancer cells that can also re-sensitize to cisplatin.
METHODS: We used lung and ovarian cancer cell lines with acquired resistance to cisplatin together with drug sensitivity assays, conducted both with monotherapies and cisplatin combinations.
RESULTS: We show that cancer cell lines with acquired resistance to cisplatin have altered levels of enzymes involved in glutamine metabolism, which can result in differential sensitivity to targeted agents. We show that expression of one of these enzymes-the glutamate-cystine antiporter SLC7A11, up-regulated 6-fold in a cisplatin-resistant lung cancer cell line-has potential prognostic significance in lung cancer but not ovarian cancer. After identifying a common dependency of cisplatin-resistant cancer cells upon extracellular glutamine, we then evaluate the utility of the long-standing anti-leukemic therapy asparaginase (ASNase)-which possesses both asparaginase and glutaminase activity-as a potential approach. We show ASNase preferentially inhibits the proliferation of cisplatin-resistant cancer cells and can potentially re-sensitize these cells to cisplatin.
CONCLUSIONS: Our results underpin the prevalence of altered metabolism in cisplatin-resistant cells and highlight the potential utility of re-purposing ASNase to target these cells, warranting further investigation.

Keywords:  SLC7A11; asparaginase (ASNase); chemoresistance; cisplatin; glutamine; metabolic rewiring

DOI:  https://doi.org/10.1111/fcp.70044
Int J Clin Oncol. 2025 Aug 12.

Clinical and biological impact of SNAT7 in lung adenocarcinoma: implications for prognosis and treatment.

Asato Hashinokuchi, Naoki Haratake, Yuya Ono, Takumi Tomonaga, Giacomo Bassi, Kyoto Matsudo, Fumihiko Kinoshita, Taichi Matsubara, Mikihiro Kohno, Tomoyoshi Takenaka, Yoshinao Oda, Tomoharu Yoshizumi.

   BACKGROUND: Glutamine metabolism plays a crucial role in cancer cell proliferation and modulates the tumour microenvironment. High expression of glutamine transporters is associated with poor prognosis in non-small cell lung cancer. SNAT7, encoded by SLC38A7, facilitates glutamine transport from lysosomes. However, its function and clinical significance in lung adenocarcinoma remain unclear.
MATERIALS AND METHODS: Immunohistochemistry (IHC) was performed with samples from 373 patients with completely resected lung adenocarcinoma, and the association between SNAT7 expression, clinicopathological features, and prognosis was examined. In addition, the biological findings were investigated in lung adenocarcinoma cell lines.
RESULTS: Based on IHC analysis, we classified patients into high (n = 226, 60.6%) and low SNAT7 expression (n = 147, 39.4%) groups. High SNAT7 expression was substantially associated with male sex, smoking status, high maximum standardised uptake value, advanced pathological stage, and pleural, lymphatic, and vascular invasion, compared to low SNAT7 expression. Patients with high SNAT7 expression demonstrated substantially worse recurrence-free survival (RFS) and overall survival rates. Multivariable analysis revealed that high SNAT7 expression was an independent prognostic factor for RFS. In addition, SLC38A7 knockdown induced a decrease in proliferation with G1 arrest in lung adenocarcinoma cell lines.
CONCLUSION: Our findings demonstrate that SNAT7 plays a pivotal role in promoting tumour malignancy and is significantly associated with poor prognosis in lung adenocarcinoma. These findings suggest that SNAT7 is a potential therapeutic target in lung adenocarcinoma.

Keywords:  Cancer metabolism; Glutamine transporter; Lung adenocarcinoma; SLC38A7; SNAT7

DOI:  https://doi.org/10.1007/s10147-025-02851-w
Iran J Basic Med Sci. 2025 ;28(9): 1129-1139

Ketone body, as an emerging modulator of metabolic reprogramming and epigenetics in breast cancer.

Fatemeh Mehdikhani, Sadegh Rajabi, Maryam Mohammadlou, Marc Maresca, Rasoul Baharlou.

  The metabolic profile of cancer cells, notably their reliance on glucose as a primary energy source for proliferation, sets them apart from normal cells. This metabolic dependency may significantly affect their invasive potential when an adequate glucose supply is available. Moreover, emerging evidence underscores the critical role of metabolism in determining the epigenetic landscape of cells. To limit the glucose supply and alter cancer cell metabolism, researchers have investigated ketogenic diets as an alternative energy source for cancer cells and providing a promising strategy to combat cancers. However, controversial findings in the literature suggest a direct relationship between the use of ketone bodies in cancer cells and the augmentation of invasiveness. Additionally, studies indicate that using ketone bodies as an energy source can influence the epigenetic patterns of tumor cells. Breast cancer cells show a unique metabolism by which the cancer cells adapt to various conditions. This paper aims to review the metabolic characteristics of breast tumors, focusing on the ketone body metabolism in this cancer and the complex interplay between ketone bodies and the epigenetic changes in this cancer.

Keywords:  Breast cancer; Epigenetics; Histone modifications; Ketone bodies; Metabolism

DOI:  https://doi.org/10.22038/ijbms.2025.84064.18185
Cancer Biol Ther. 2025 Dec;26(1): 2546219

Hypoxia-induced PYCR1 regulates glycolysis and histone lactylation to promote bladder cancer progression and metastasis via SLC6A14/Glutamine metabolism.

Zhuo Li, Qinghua Jiang, Quan Yang, Yujie Zhou, Jiansong Wang.

  Hypoxia-induced Pyrroline-5-Carboxylate Reductase 1 (PYCR1) is implicated in bladder cancer (BC), but its specific role remains elusive. This study investigated how PYCR1 promotes BC progression through glycolysis, histone H3 Lysine 18 Lactylation (H3K18la), and Solute Carrier Family 6 Member 14 (SLC6A14)-driven glutamine catabolism. Here, BC cell lines were cultured under hypoxia to evaluate changes in PYCR1 expression, glycolysis, and lactate production. The xenograft and metastasis models in nude mice were used to validate the role of the PYCR1/H3K18la/SLC6A14 axis in BC progression. GEPIA Bioinformatics database data showed that PYCR1 was upregulated in BC and was associated with poor prognosis. The PYCR1 positive expression rate in BC tissues was increased. Hypoxia induced PYCR1 expression in BC cells, enhancing glycolysis and lactate production, which increased H3K18la levels. Upregulated SLC6A14 expression promoted glutamine catabolism and enhanced BC cell proliferation, migration, and invasion. PYCR1 knockdown inhibited H3K18la levels, SLC6A14 expression, and BC cell aggressiveness; SLC6A14 overexpression reversed these effects. In vivo experiments confirmed that the PYCR1/H3K18la/SLC6A14 axis is critical for hypoxia-driven BC growth and metastasis. In summary, Hypoxia-induced PYCR1 enhances glycolysis, leading to increased lactate production and elevated H3K18la levels, which upregulates SLC6A14 transcription and glutamine catabolism, thereby promoting BC growth and metastasis.

Keywords:  Bladder cancer; H3K18la; PYCR1; SLC6A14; glutamine catabolism; glycolysis; histone lactylation; lactate

DOI:  https://doi.org/10.1080/15384047.2025.2546219
Cancer Lett. 2025 Aug 09. pii: S0304-3835(25)00547-6. [Epub ahead of print] 217977

Restricting metabolic plasticity enhances stress adaptation through the modulation of PDH and HIF1A in TRAP1-depleted colon cancer.

Hong-Yuan Tsai, Miao-Hsueh Chen, Jihye Yun, Lisa A Lai, John F Valentine, Mary P Bronner, Teresa A Brentnall, Sheng Pan, Ru Chen.

  Metabolic plasticity allows cancer cells to survive under adverse conditions. To investigate the role of mitochondrial chaperone tumor necrosis factor receptor-associated protein 1 (TRAP1) in this process, we used CRISPR/Cas9 mediated genetic deletion to knock out (KO) TRAP1 in colon cancer cells. Depletion of TRAP1 triggered a series of events: induced metabolic reprogramming, increased glycolytic flux, downregulation of mitochondrial complex I, and elevated ROS generation. TRAP1-deficient cells showed tolerance to Oxidative Phosphorylation (OXPHOS) inhibitors and exhibited a higher extracellular acidification rate (ECAR). Additionally, TRAP1 depletion activated hypoxia response elements (HREs) and upregulated HIF1A target genes such as GLUT1 and MCT1. Furthermore, pyruvate dehydrogenase kinases 1 (PDK1) was upregulated in KO cells, leading to the inactivation of the tricarboxylic acid (TCA) cycle enzyme, pyruvate dehydrogenase (PDH). This metabolic shift towards glycolytic metabolism resulted in increased glycolytic metabolism, elevated lactic acid production, and higher glucose consumption, making TRAP1-depleted cancer cells more dependent on this altered metabolism for survival. Treatment with DCA, a PDK inhibitor, restored PDH activity, exacerbated oxidative stress, and increased cell death in KO cells. Our study here sheds light on how TRAP1 depletion affects metabolic plasticity, driving colon cancer cells to adapt to metabolic and oxidative stress. These findings highlight TRAP1 as a promising therapeutic target for manipulating metabolic plasticity and overcoming drug resistance in cancer therapy.

Keywords:  HIF1A; Metabolism; PDH; ROS; TRAP1; mitochondria

DOI:  https://doi.org/10.1016/j.canlet.2025.217977
Nat Commun. 2025 Aug 15. 16(1): 7611

Androgens drive SLC1A5-dependent metabolic reprogramming in polycystic ovary syndrome.

Yishu Wang, Jiaying Wu, Gaochen Zhang, Yan Shi, Yicong Meng, Pingping Lv, Weiwei Huang, Yunfei Su, Zhiyang Zhou, Bo Wang, Xiaojun Chen, Chengliang Zhou, Jiexue Pan, Li Jin, Xiaotao Wang, Yanting Wu, Jianzhong Sheng, Xinmei Liu, Yu Zhang, Guolian Ding, Chuanjin Yu, Hefeng Huang.

Polycystic ovary syndrome is the primary cause of female infertility. Growing evidence suggests that dysregulation of amino acid metabolism plays a significant role in the onset and progression. However, the underlying mechanism remains unclear. In this study, we conduct targeted metabolite profiling of human follicular fluid and granulosa cells. A significant increase in glutamine uptake is observed in patients with hyperandrogenic polycystic ovary syndrome, mediated by the upregulation of SLC1A5, a specific glutamine transporter. We find that androgen excess primarily activates SLC1A5 expression. Furthermore, SLC1A5 overexpression in female mice induces polycystic ovary syndrome-like phenotypes, including hyperandrogenism and abnormal follicle development. Additionally, the pharmacological blockade of SLC1A5 provides reproductive benefits to mice exhibiting polycystic ovary syndrome-like symptoms. Mechanistically, we show that elevated flux of Gln-derived α-ketoglutarate enhances HDAC5 expression and suppresses acetylation on histone 3 lysine residue 14 and lysine residue 56. The reduction in acetylation level is associated with the downregulation of several genes related to folliculogenesis, including CYP19A1, thereby exacerbating androgenic homeostasis imbalance. These findings indicate that androgen-induced aberrant glutamine uptake via SLC1A5 is crucial for the development and progression of polycystic ovary syndrome, suggesting pharmacological blockade of SLC1A5 as a potential therapeutic strategy.

DOI: https://doi.org/10.1038/s41467-025-62951-z
Int J Mol Sci. 2025 Jul 26. pii: 7242. [Epub ahead of print]26(15):

Molecular Mechanisms and Clinical Implications of Complex Prehabilitation in Colorectal Cancer Surgery: A Comprehensive Review.

Jakub Włodarczyk.

  Colorectal cancer (CRC) remains a leading cause of cancer morbidity and mortality worldwide, especially in older adults where frailty complicates treatment outcomes. Multimodal prehabilitation-comprising nutritional support, physical exercise, and psychological interventions-has emerged as a promising strategy to enhance patients' resilience before CRC surgery. Clinical studies demonstrate that prehabilitation significantly reduces postoperative complications, shortens hospital stays, and improves functional recovery. Nutritional interventions focus on counteracting malnutrition and sarcopenia through tailored dietary counseling, protein supplementation, and immunonutrients like arginine and glutamine. Physical exercise enhances cardiorespiratory fitness and muscle strength while modulating immune and metabolic pathways critical for surgical recovery. Psychological support reduces anxiety and depression, promoting mental resilience that correlates with better postoperative outcomes. Despite clear clinical benefits, the molecular mechanisms underlying prehabilitation's effects-such as inflammation modulation, immune activation, and metabolic rewiring-remain poorly understood. This review addresses this knowledge gap by exploring potential biological pathways influenced by prehabilitation, aiming to guide more targeted, personalized approaches in CRC patient management. Advancing molecular insights may optimize prehabilitation protocols and improve survival and quality of life for CRC patients undergoing surgery.

Keywords:  colorectal cancer; nutrition; physical intervention; prehabilitation; psychological intervention

DOI:  https://doi.org/10.3390/ijms26157242
Arch Endocrinol Metab. 2025 Aug 13.

MiR-195-5p regulates oxidative stress and aerobic metabolism by directly downregulating GLS2 in high glucose-induced human lens epithelial cells.

Ling Yao, Meng Yue, Yuxian Sun, Juan Li, Qi Zhou, Ning Li, Xiaoli Yue, Junyan Hu, Linkang Yin, Zhengyang Xu, Xiang Gao, Wei Zhang, Ziqing Gao.

   OBJECTIVE: To investigated how miR-195-5p affects oxidative stress and modulates aerobic metabolism.
MATERIALS AND METHODS: MiR-195-5p plus GLS2 mRNA was identified by conducting real-time quantitative polymerase chain reaction. Western blotting was conducted to determine GLS2 protein expression. Corresponding kits were used to determine the concentrations of glutamate, reduced glutathione, oxidized glutathione, a-ketoglutarate, and adenosine triphosphate. The cell counting Kit-8 assay was performed to determine viability. Flow cytometry assay was performed to measure the reactive oxygen species content. Finally, a dual-luciferase reporter assay was conducted to confirm the interaction of miR-195-5p with GLS2 mRNA in the 3'UTR.
RESULTS: In high glucose-induced SRA01/04 cells, miR-195-5p was overexpressed, and GLS2 was downregulated. When miR-195-5p was upregulated, the levels of glutamate, reduced glutathione, a-ketoglutarate, and adenosine triphosphate, along with the reduced glutathione-to-oxidized glutathione ratio decreased, whereas the reactive oxygen species levels increased. Oxidative stress was ameliorated after miR-195-5p was downregulated. MiR-195-5p adversely controls the expression of GLS2 mRNA and protein. MiR-195-5p exacerbates oxidative damage and hinders aerobic metabolism by downregulating GLS2.
CONCLUSION: Oxidative stress and aerobic metabolism in human lens epithelial cells were found to be regulated by miR-195-5p after the downregulation of GLS2.

Keywords:  Cataract; Glutaminase; Lens Epithelial Cells; MicroRNAs; Oxidative stress

DOI:  https://doi.org/10.20945/2359-4292-2024-0469
Front Syst Biol. 2024 ;4 1412931

Modeling uncertainty: the impact of noise in T cell differentiation.

David Martínez-Méndez, Carlos Villarreal, Leonor Huerta.

   Background: The regulatory mechanisms guiding CD4 T cell differentiation are complex and are further influenced by intrinsic cell variability along with that of microenvironmental cues, such as cytokine and nutrient availability.
Objective: This study aims to expand our understanding of CD4 T cell differentiation by examining the influence of intrinsic noise on cell fate.
Methodology: A model based on a complex regulatory network of early signaling events involved in CD4 T cell activation and differentiation was described in terms of a set of stochastic differential equation to assess the effect of noise intensity on differentiation efficiency to the Th1, Th2, Th17, Treg, and TFH effector phenotypes under defined cytokine and nutrient conditions.
Results: The increase of noise intensity decreases differentiation efficiencies. In a microenvironment of Th1-inducing cytokines and optimal nutrient conditions, noise levels of 3 % , 5 % and 10 % render Th1 differentiation efficiencies of 0.87, 0.76 and 0.62, respectively, underscoring the sensitivity of the network to random variations. Further increments of noise reveal that the network is relatively stable until noise levels of 20 % , where the resulting cell phenotypes becomes heterogeneous. Notably, Treg differentiation showed the highest robustness to noise perturbations. A combined Th1-Th2 cytokine environment with optimal nutrient levels induces a dominant Th1 phenotype; however, removal of glutamine shifts the balance towards the Th2 phenotype at all noise levels, with an efficiency similar to that obtained under Th2-only cytokine conditions. Similarly, combinations of Th1/Treg and Treg/Th17-inducing cytokines along with the removal of either tryptophan or oxygen shift the dominant Th1 and Treg phenotypes towards Treg and Th17 respectively. Model results are consistent with differentiation efficiency patterns obtained under well-controlled experimental settings reported in the literature.
Conclusion: The stochastic CD4 T cell mathematical model presented here demonstrates a noise-dependent modulation of T cell differentiation induced by cytokines and nutrient availability. Modeling results can be explained by the network topology, which assures that the system will arrive at stable states of cell functionality despite variable levels of biological intrinsic noise. Moreover, the model provides insights into the robustness of the T cell differentiation process.

Keywords:  CD4 T lymphocytes; complex network; cytokines; differentiation; glutamine; hypoxia; noise; stochastic process

DOI:  https://doi.org/10.3389/fsysb.2024.1412931