bims-glucam 2024-01-28 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024‒01‒28
twenty papers selected by
Sreeparna Banerjee, Middle East Technical University

Glutamine Metabolism Promotes Renal Fibrosis through Regulation of Mitochondrial Energy Generation and Mitochondrial Fission.
Biomimetic Nanomedicine Targeting Orchestrated Metabolism Coupled with Regulatory Factors to Disrupt the Metabolic Plasticity of Breast Cancer.
TIM-3/Galectin-9 interaction and glutamine metabolism in AML cell lines, HL-60 and THP-1.
The impact of broad glutamine metabolism inhibition on the tumor microenvironment.
Association of Glutamine and Glutamate Metabolism with Mortality among Patients at Nutritional Risk-A Secondary Analysis of the Randomized Clinical Trial EFFORT.
Melatonin: a modulator in metabolic rewiring in T-cell malignancies.
Metabolic heterogeneity in cancer.
Metabolic alterations in hereditary and sporadic renal cell carcinoma.
Nano-medicine therapy reprogramming metabolic network of tumor microenvironment: new opportunity for cancer therapies.
Investigation of Roles of SLC38A1 in Proliferation and Differentiation of Mouse Tongue Epithelium and Expression in Human Oral Tongue Squamous Cell Carcinoma.
Amino Acid Transporters Proteins Involved in the Glutamate-Glutamine Cycle and Their Alterations in Murine Models of Alzheimer's Disease.
Targeting the Metabolic Paradigms in Cancer and Diabetes.
The Role of Amino Acids in Non-Enzymatic Antioxidant Mechanisms in Cancer: A Review.
The redox requirement and regulation during cell proliferation.
A mouse model to study glutathione limitation in vivo.
Thyroid cancer cell metabolism: A glance into cell culture system-based metabolomics approaches.
The Multifaceted Roles of NRF2 in Cancer: Friend or Foe?
Oral glutamine: Is there a role in the amelioration of radiation-induced mucositis? A prospective case-control study at a tertiary care centre in North India.
Comprehensive review of amino acid transporters as therapeutic targets.
Glutathione Reductase Expression and Its Prognostic Significance in Colon Cancer.

Int J Biol Sci. 2024 ;20(3): 987-1003

Glutamine Metabolism Promotes Renal Fibrosis through Regulation of Mitochondrial Energy Generation and Mitochondrial Fission.

Yang Cai, Beichen Tian, Yuanjun Deng, Lele Liu, Chunjiang Zhang, Wei Peng, Qian Li, Tianjing Zhang, Min Han, Gang Xu.

  Fibroblast activation and proliferation is an essential phase in the progression of renal fibrosis. Despite the recognized significance of glutamine metabolism in cellular growth and proliferation, its precise pathophysiological relevance in renal fibrosis remains uncertain. Therefore, this study aims to investigate the involvement of glutamine metabolism in fibroblast activation and its possible mechanism. Our findings highlight the importance of glutamine metabolism in fibroblast activation and reveal that patients with severe fibrosis exhibit elevated serum glutamine levels and increased expression of kidney glutamine synthetase. Furthermore, the deprivation of glutamine metabolism in vitro and in vivo could inhibit fibroblast activation, thereby ameliorating renal fibrosis. It was also detected that glutamine metabolism is crucial for maintaining mitochondrial function and morphology. These effects may partially depend on the metabolic intermediate α-ketoglutaric acid. Moreover, glutamine deprivation led to upregulated mitochondrial fission in fibroblasts and the activation of the mammalian target of rapamycin / mitochondrial fission process 1 / dynamin-related protein 1 pathway. Thus, these results provide compelling evidence that the modulation of glutamine metabolism initiates the regulation of mitochondrial function, thereby facilitating the progression of renal fibrosis. Consequently, targeting glutamine metabolism emerges as a novel and promising avenue for therapeutic intervention and prevention of renal fibrosis.

Keywords:  Fibroblasts; Glutamine; Mitochondria; Mitochondrial fission; Renal fibrosis; α-ketoglutaric acid

DOI:  https://doi.org/10.7150/ijbs.89960
ACS Nano. 2024 Jan 26.

Biomimetic Nanomedicine Targeting Orchestrated Metabolism Coupled with Regulatory Factors to Disrupt the Metabolic Plasticity of Breast Cancer.

Lingtong Meng, Jingpeng Yang, Yang Gao, Qinyan Cao, Shunjie Jiang, Yuyang Xiao, Haoran Wang, Wenzheng Liu, Ahu Yuan, Yanan Li, He Huang.

  Targeting nutrient metabolism has been proposed as an effective therapeutic strategy to combat breast cancer because of its high nutrient requirements. However, metabolic plasticity enables breast cancer cells to survive under unfavorable starvation conditions. The key mammalian target regulators rapamycin (mTOR) and hypoxia-inducible-factor-1 (HIF-1) tightly link the dynamic metabolism of glutamine and glucose to maintain nutrient flux. Blocking nutrient flow also induces autophagy to recycle nutrients in the autophagosome, which exacerbates metastasis and tumor progression. Compared to other common cancers, breast cancer is even more dependent on mTOR and HIF-1 to orchestrate the metabolic network. Therefore, we develop a cascade-boosting integrated nanomedicine to reprogram complementary metabolism coupled with regulators in breast cancer. Glucose oxidase efficiently consumes glucose, while the delivery of rapamycin inside limits the metabolic flux of glutamine and uncouples the feedback regulation of mTOR and HIF-1. The hydroxyl radical generated in a cascade blocks the later phase of autophagy without nutrient recycling. This nanomedicine targeting orchestrated metabolism can disrupt the coordination of glucose, amino acids, nucleotides, lipids, and other metabolic pathways in breast cancer tissues, effectively improving the durable antitumor effect and prognosis of breast cancer. Overall, the cascade-boosting integrated system provides a viable strategy to address cellular plasticity and efficient enzyme delivery.

Keywords:  autophagy; glucose metabolism; glutamine metabolism; metabolic plasticity; nanomedicine

DOI:  https://doi.org/10.1021/acsnano.3c10129
BMC Cancer. 2024 Jan 24. 24(1): 125

TIM-3/Galectin-9 interaction and glutamine metabolism in AML cell lines, HL-60 and THP-1.

Hooriyeh Shapourian, Mustafa Ghanadian, Nahid Eskandari, Abolfazl Shokouhi, Gülderen Yanikkaya Demirel, Alexandr V Bazhin, Mazdak Ganjalikhani-Hakemi.

  BACKGROUND: T cell immunoglobulin and mucin-domain containing-3 (TIM-3) is a cell surface molecule that was first discovered on T cells. However, recent studies revealed that it is also highly expressed in acute myeloid leukemia (AML) cells and it is related to AML progression. As, Glutamine appears to play a prominent role in malignant tumor progression, especially in their myeloid group, therefore, in this study we aimed to evaluate the relation between TIM-3/Galectin-9 axis and glutamine metabolism in two types of AML cell lines, HL-60 and THP-1.METHODS: Cell lines were cultured in RPMI 1640 which supplemented with 10% FBS and 1% antibiotics. 24, 48, and 72 h after addition of recombinant Galectin-9 (Gal-9), RT-qPCR analysis, RP-HPLC and gas chromatography techniques were performed to evaluate the expression of glutaminase (GLS), glutamate dehydrogenase (GDH) enzymes, concentration of metabolites; Glutamate (Glu) and alpha-ketoglutarate (α-KG) in glutaminolysis pathway, respectively. Western blotting and MTT assay were used to detect expression of mammalian target of rapamycin complex (mTORC) as signaling factor, GLS protein and cell proliferation rate, respectively.
RESULTS: The most mRNA expression of GLS and GDH in HL-60 cells was seen at 72 h after Gal-9 treatment (p = 0.001, p = 0.0001) and in THP-1 cell line was observed at 24 h after Gal-9 addition (p = 0.001, p = 0.0001). The most mTORC and GLS protein expression in HL-60 and THP-1 cells was observed at 72 and 24 h after Gal-9 treatment (p = 0.0001), respectively. MTT assay revealed that Gal-9 could promote cell proliferation rate in both cell lines (p = 0.001). Glu concentration in HL-60 and α-KG concentration in both HL-60 (p = 0.03) and THP-1 (p = 0.0001) cell lines had a decreasing trend. But, Glu concentration had an increasing trend in THP-1 cell line (p = 0.0001).
CONCLUSION: Taken together, this study suggests TIM-3/Gal-9 interaction could promote glutamine metabolism in HL-60 and THP-1 cells and resulting in AML development.

Keywords:  Acute myeloid leukemia (AML); Galectin-9 (Gal-9); Glutamate dehydrogenase (GDH); Glutaminase (GLS); Glutamine metabolism; T cell immunoglobulin and mucin-domain containing-3 (TIM-3)

DOI:  https://doi.org/10.1186/s12885-024-11898-3
Genes Dis. 2024 May;11(3): 100984

The impact of broad glutamine metabolism inhibition on the tumor microenvironment.

Tianhe Li, Yun-Ta Chuang, Tian-Li Wang.

DOI: https://doi.org/10.1016/j.gendis.2023.05.003
Nutrients. 2024 Jan 10. pii: 222. [Epub ahead of print]16(2):

Association of Glutamine and Glutamate Metabolism with Mortality among Patients at Nutritional Risk-A Secondary Analysis of the Randomized Clinical Trial EFFORT.

Carla Wunderle, Diana von Arx, Sydney Chiara Mueller, Luca Bernasconi, Peter Neyer, Pascal Tribolet, Zeno Stanga, Beat Mueller, Philipp Schuetz.

  Glutamine and its metabolite glutamate serve as the main energy substrates for immune cells, and their plasma levels drop during severe illness. Therefore, glutamine supplementation in the critical care setting has been advocated. However, little is known about glutamine metabolism in severely but not critically ill medical patients. We investigated the prognostic impact of glutamine metabolism in a secondary analysis of the Effect of Early Nutritional Support on Frailty, Functional Outcomes, and Recovery of Malnourished Medical Inpatients Trial (EFFORT), a randomized controlled trial comparing individualized nutritional support to usual care in patients at nutritional risk. Among 234 patients with available measurements, low plasma levels of glutamate were independently associated with 30-day mortality (adjusted HR 2.35 [95% CI 1.18-4.67, p = 0.015]). The impact on mortality remained consistent long-term for up to 5 years. No significant association was found for circulating glutamine levels and short- or long-term mortality. There was no association of glutamate nor glutamine with malnutrition parameters or with the effectiveness of nutritional support. This secondary analysis found glutamate to be independently prognostic among medical inpatients at nutritional risk but poorly associated with the effectiveness of nutritional support. In contrast to ICU studies, we found no association between glutamine and clinical outcome.

Keywords:  biomarker; glutamate; glutamine; individualized nutrition support; malnutrition; polymorbid patient

DOI:  https://doi.org/10.3390/nu16020222
Front Oncol. 2023 ;13 1248339

Melatonin: a modulator in metabolic rewiring in T-cell malignancies.

Seema Rai, Gunja Roy, Younis Ahmad Hajam.

  Melatonin, (N-acetyl-5-methoxytryptamine) an indoleamine exerts multifaced effects and regulates numerous cellular pathways and molecular targets associated with circadian rhythm, immune modulation, and seasonal reproduction including metabolic rewiring during T cell malignancy. T-cell malignancies encompass a group of hematological cancers characterized by the uncontrolled growth and proliferation of malignant T-cells. These cancer cells exhibit a distinct metabolic adaptation, a hallmark of cancer in general, as they rewire their metabolic pathways to meet the heightened energy requirements and biosynthesis necessary for malignancies is the Warburg effect, characterized by a shift towards glycolysis, even when oxygen is available. In addition, T-cell malignancies cause metabolic shift by inhibiting the enzyme pyruvate Dehydrogenase Kinase (PDK) which in turn results in increased acetyl CoA enzyme production and cellular glycolytic activity. Further, melatonin plays a modulatory role in the expression of essential transporters (Glut1, Glut2) responsible for nutrient uptake and metabolic rewiring, such as glucose and amino acid transporters in T-cells. This modulation significantly impacts the metabolic profile of T-cells, consequently affecting their differentiation. Furthermore, melatonin has been found to regulate the expression of critical signaling molecules involved in T-cell activations, such as CD38, and CD69. These molecules are integral to T-cell adhesion, signaling, and activation. This review aims to provide insights into the mechanism of melatonin's anticancer properties concerning metabolic rewiring during T-cell malignancy. The present review encompasses the involvement of oncogenic factors, the tumor microenvironment and metabolic alteration, hallmarks, metabolic reprogramming, and the anti-oncogenic/oncostatic impact of melatonin on various cancer cells.

Keywords:  T-cell exhaustion; T-cell malignancy; cancer; melatonin; metabolic rewiring; tumor microenvironment

DOI:  https://doi.org/10.3389/fonc.2023.1248339
Nat Metab. 2024 Jan 24.

Metabolic heterogeneity in cancer.

Margherita Demicco, Xiao-Zheng Liu, Katharina Leithner, Sarah-Maria Fendt.

Cancer cells rewire their metabolism to survive during cancer progression. In this context, tumour metabolic heterogeneity arises and develops in response to diverse environmental factors. This metabolic heterogeneity contributes to cancer aggressiveness and impacts therapeutic opportunities. In recent years, technical advances allowed direct characterisation of metabolic heterogeneity in tumours. In addition to the metabolic heterogeneity observed in primary tumours, metabolic heterogeneity temporally evolves along with tumour progression. In this Review, we summarize the mechanisms of environment-induced metabolic heterogeneity. In addition, we discuss how cancer metabolism and the key metabolites and enzymes temporally and functionally evolve during the metastatic cascade and treatment.

DOI: https://doi.org/10.1038/s42255-023-00963-z
Nat Rev Nephrol. 2024 Jan 22.

Metabolic alterations in hereditary and sporadic renal cell carcinoma.

Nathan J Coffey, M Celeste Simon.

Kidney cancer is the seventh leading cause of cancer in the world, and its incidence is on the rise. Renal cell carcinoma (RCC) is the most common form and is a heterogeneous disease comprising three major subtypes that vary in their histology, clinical course and driver mutations. These subtypes include clear cell RCC, papillary RCC and chromophobe RCC. Molecular analyses of hereditary and sporadic forms of RCC have revealed that this complex and deadly disease is characterized by metabolic pathway alterations in cancer cells that lead to deregulated oxygen and nutrient sensing, as well as impaired tricarboxylic acid cycle activity. These metabolic changes facilitate tumour growth and survival. Specifically, studies of the metabolic features of RCC have led to the discovery of oncometabolites - fumarate and succinate - that can promote tumorigenesis, moonlighting functions of enzymes, and substrate auxotrophy owing to the disruption of pathways that enable the production of arginine and cholesterol. These metabolic alterations within RCC can be exploited to identify new therapeutic targets and interventions, in combination with novel approaches that minimize the systemic toxicity of metabolic inhibitors and reduce the risk of drug resistance owing to metabolic plasticity.

DOI: https://doi.org/10.1038/s41581-023-00800-2
J Drug Target. 2024 Jan 22. 1-47

Nano-medicine therapy reprogramming metabolic network of tumor microenvironment: new opportunity for cancer therapies.

Xiaojie Zhang, Min An, Juntao Zhang, Yumeng Zhao, Yanhua Liu.

  Metabolic heterogeneity is one of the characteristics of tumor cells. In order to adapt to the tumor microenvironment of hypoxia, acidity and nutritional deficiency, tumor cells have undergone extensive metabolic reprogramming. Metabolites involved in tumor cell metabolism are also very different from normal cells, such as a large number of lactate and adenosine. Metabolites play an important role in regulating the whole tumor microenvironment. Taking metabolites as the target, it aims to change the metabolic pattern of tumor cells again, destroy the energy balance it maintains, activate the immune system, and finally kill tumor cells. In this paper, the regulatory effects of metabolites such as lactate, glutamine, arginine, tryptophan, fatty acids and adenosine were reviewed, and the related targeting strategies of nano-medicines were summarized, and the future therapeutic strategies of nano-drugs were discussed. The abnormality of tumor metabolites caused by tumor metabolic remodeling not only changes the energy and material supply of tumor, but also participates in the regulation of tumor-related signal pathways, which plays an important role in the survival, proliferation, invasion and metastasis of tumor cells. Regulating the availability of local metabolites is a new aspect that affects tumor progress.

Keywords:  immune cells; metabolite; nano-medicine; tumor microenvironment

DOI:  https://doi.org/10.1080/1061186X.2024.2309565
Cancers (Basel). 2024 Jan 18. pii: 405. [Epub ahead of print]16(2):

Investigation of Roles of SLC38A1 in Proliferation and Differentiation of Mouse Tongue Epithelium and Expression in Human Oral Tongue Squamous Cell Carcinoma.

Dipak Sapkota, Daxin Wang, Olaf Schreurs, Evan M Vallenari, Sushma Pandey Dhakal, Thomas Küntziger, Burcu Sengüven Toközlü, Tor Paaske Utheim, Farrukh Abbas Chaudhry.

  The aerobic glycolytic pathway, boosting lactate formation, and glutamine addiction are two hallmarks of cancer pathophysiology. Consistent with this, several cell membrane glutamine transporters, belonging to different solute carrier (SLC) families, have been shown to be upregulated in a cell-specific manner to furnish the cells with glutamine and glutamine-derived metabolic intermediates. Among them, the system A transporter Slc38a1 has a higher affinity for glutamine compared to other SLC transporters, and it undergoes highly multifaceted regulation at gene and protein levels. The current study aimed to investigate the functional role of Slc38a1 in the proliferation and maturation of the mouse tongue epithelium. Secondly, we aimed to examine the expression of SLC38A1 and its regulation in human tongue oral squamous cell carcinoma (OTSCC). Employing Slc38a1 wild-type and knockout mice, we showed that Slc38a1 was not directly linked to the regulation of the proliferation and differentiation of the mouse tongue epithelium. External transcriptomic datasets and Western blot analyses showed upregulation of SLC38A1 mRNA/protein in human OTSCC and oral cancer cell lines as compared to the corresponding controls. Further, an investigation of external datasets indicated that mechanisms other than the amplification of the SLC38A1 chromosomal locus or hypomethylation of the SLC38A1 promoter region might be important for the upregulation of SLC38A1 in OTSCC.

Keywords:  SNAT1; Slc38a1; glutamine; head and neck cancer; maturation; methylation; oral cancer

DOI:  https://doi.org/10.3390/cancers16020405
Mol Neurobiol. 2024 Jan 26.

Amino Acid Transporters Proteins Involved in the Glutamate-Glutamine Cycle and Their Alterations in Murine Models of Alzheimer's Disease.

Diana Laura Vázquez-Durán, Arturo Ortega, Angelina Rodríguez.

  The brain's ability to integrate external stimuli and generate responses is highly complex. While these mechanisms are not completely understood, current evidence suggests that alterations in cellular metabolism and microenvironment are involved in some dysfunctions as complex as Alzheimer's disease. This pathology courses with defects in the establishment of chemical synapses, which is dependent on the production and supply of neurotransmitters like glutamate and its recycling through the glutamate-glutamine cycle. Alterations in the expression and function of the amino acid transporters proteins involved in this cycle have recently been reported in different stages of Alzheimer's disease. Most of these data come from patients in advanced stages of the disease or post-mortem, due to the ethical and technical limitations of human studies. Therefore, genetically modified mouse models have been an excellent tool to analyze metabolic and even behavioral parameters that are very similar to those that develop in Alzheimer's disease, even at presymptomatic stages. Hence, this paper analyzes the role of glutamate metabolism and its intercellular trafficking in excitatory synapses from different approaches using transgenic mouse models; such an analysis will contribute to our present understanding of AD.

Keywords:  Alzheimer’s disease; Amino acid transporter; Glutamate-Glutamine Cycle

DOI:  https://doi.org/10.1007/s12035-024-03966-3
Biomedicines. 2024 Jan 17. pii: 211. [Epub ahead of print]12(1):

Targeting the Metabolic Paradigms in Cancer and Diabetes.

Mira Bosso, Dania Haddad, Ashraf Al Madhoun, Fahd Al-Mulla.

  Dysregulated metabolic dynamics are evident in both cancer and diabetes, with metabolic alterations representing a facet of the myriad changes observed in these conditions. This review delves into the commonalities in metabolism between cancer and type 2 diabetes (T2D), focusing specifically on the contrasting roles of oxidative phosphorylation (OXPHOS) and glycolysis as primary energy-generating pathways within cells. Building on earlier research, we explore how a shift towards one pathway over the other serves as a foundational aspect in the development of cancer and T2D. Unlike previous reviews, we posit that this shift may occur in seemingly opposing yet complementary directions, akin to the Yin and Yang concept. These metabolic fluctuations reveal an intricate network of underlying defective signaling pathways, orchestrating the pathogenesis and progression of each disease. The Warburg phenomenon, characterized by the prevalence of aerobic glycolysis over minimal to no OXPHOS, emerges as the predominant metabolic phenotype in cancer. Conversely, in T2D, the prevailing metabolic paradigm has traditionally been perceived in terms of discrete irregularities rather than an OXPHOS-to-glycolysis shift. Throughout T2D pathogenesis, OXPHOS remains consistently heightened due to chronic hyperglycemia or hyperinsulinemia. In advanced insulin resistance and T2D, the metabolic landscape becomes more complex, featuring differential tissue-specific alterations that affect OXPHOS. Recent findings suggest that addressing the metabolic imbalance in both cancer and diabetes could offer an effective treatment strategy. Numerous pharmaceutical and nutritional modalities exhibiting therapeutic effects in both conditions ultimately modulate the OXPHOS-glycolysis axis. Noteworthy nutritional adjuncts, such as alpha-lipoic acid, flavonoids, and glutamine, demonstrate the ability to reprogram metabolism, exerting anti-tumor and anti-diabetic effects. Similarly, pharmacological agents like metformin exhibit therapeutic efficacy in both T2D and cancer. This review discusses the molecular mechanisms underlying these metabolic shifts and explores promising therapeutic strategies aimed at reversing the metabolic imbalance in both disease scenarios.

Keywords:  cancer; glutaminolysis; insulin resistance; metabolic shift; mitochondria; nutritional adjuvants; oxidative phosphorylation; therapy; type 2 diabetes

DOI:  https://doi.org/10.3390/biomedicines12010211
Metabolites. 2023 Dec 31. pii: 28. [Epub ahead of print]14(1):

The Role of Amino Acids in Non-Enzymatic Antioxidant Mechanisms in Cancer: A Review.

Elena I Dyachenko, Lyudmila V Bel'skaya.

  Currently, the antioxidant properties of amino acids and their role in the physicochemical processes accompanying oxidative stress in cancer remain unclear. Cancer cells are known to extensively uptake amino acids, which are used as an energy source, antioxidant precursors that reduce oxidative stress in cancer, and as regulators of inhibiting or inducing tumor cell-associated gene expression. This review examines nine amino acids (Cys, His, Phe, Met, Trp, Tyr, Pro, Arg, Lys), which play a key role in the non-enzymatic oxidative process in various cancers. Conventionally, these amino acids can be divided into two groups, in one of which the activity increases (Cys, Phe, Met, Pro, Arg, Lys) in cancer, and in the other, it decreases (His, Trp, Tyr). The review examines changes in the metabolism of nine amino acids in eleven types of oncology. We have identified the main nonspecific mechanisms of changes in the metabolic activity of amino acids, and described direct and indirect effects on the redox homeostasis of cells. In the future, this will help to understand better the nature of life of a cancer cell and identify therapeutic targets more effectively.

Keywords:  amino acids; cancer; non-enzymatic antioxidant system; oxidative stress

DOI:  https://doi.org/10.3390/metabo14010028
Trends Endocrinol Metab. 2024 Jan 22. pii: S1043-2760(23)00278-3. [Epub ahead of print]

The redox requirement and regulation during cell proliferation.

Zhuoran Zhen, Jiankun Ren, Jiajun Zhu.

  The intracellular metabolic network comprises a variety of reduction-oxidation (redox) reactions that occur in a temporally and spatially distinct manner. In order to coordinate these redox processes, mammalian cells utilize a collection of electron-carrying molecules common to many redox reactions, including NAD, NADP, coenzyme Q (CoQ), and glutathione (GSH). This review considers the metabolic basis of redox regulation in the context of cell proliferation by analyzing how cells acquire and utilize electron carriers to maintain directional carbon flux, sustain reductive biosynthesis, and support antioxidant defense. Elucidating the redox requirement during cell proliferation can advance the understanding of human diseases such as cancer, and reveal effective therapeutic opportunities in the clinic.

Keywords:  CoQ; GSH; NAD; NADP; cancer; cell proliferation; metabolism; redox

DOI:  https://doi.org/10.1016/j.tem.2023.12.010
bioRxiv. 2024 Jan 09. pii: 2024.01.08.574722. [Epub ahead of print]

A mouse model to study glutathione limitation in vivo.

Rebecca C Timson, Artem Khan, Beste Uygur, Marwa Saad, Hsi-Wen Yeh, Nicole DelGaudio, Ross Weber, Hanan Alwaseem, Jing Gao, Chingwen Yang, Kıvanç Birsoy.

Glutathione (GSH) is a highly abundant tripeptide thiol that performs diverse protective and biosynthetic functions in cells. While changes in GSH availability are linked to many diseases, including cancer and neurodegenerative disorders, determining the function of GSH in physiology and disease has been challenging due to its tight regulation. To address this, we generated cell and mouse models that express a bifunctional glutathione-synthesizing enzyme from Streptococcus Thermophilus (GshF). GshF expression allows efficient production of GSH in the cytosol and mitochondria and prevents cell death in response to GSH depletion, but not ferroptosis, indicating that GSH is not a limiting factor under lipid peroxidation. CRISPR screens using engineered enzymes revealed metabolic liabilities under compartmentalized GSH depletion. Finally, GshF expression in mice is embryonically lethal but sustains postnatal viability when restricted to adulthood. Overall, our work identifies a conditional mouse model to investigate the role of GSH availability in physiology and disease.

DOI: https://doi.org/10.1101/2024.01.08.574722
Exp Cell Res. 2024 Jan 24. pii: S0014-4827(24)00026-0. [Epub ahead of print] 113936

Thyroid cancer cell metabolism: A glance into cell culture system-based metabolomics approaches.

Raziyeh Abooshahab, Fatemeh Razavi, Fatemeh Ghorbani, Koroush Hooshmand, Maryam Zarkesh, Mehdi Hedayati.

  Thyroid cancer is the most common malignancy of the endocrine system and the seventh most prevalent cancer in women worldwide. It is a complex and diverse disease characterized by heterogeneity, underscoring the importance of understanding the underlying metabolic alterations within tumor cells. Metabolomics technologies offer a powerful toolset to explore and identify endogenous and exogenous biochemical reaction products, providing crucial insights into the intricate metabolic pathways and processes within living cells. Metabolism plays a central role in cell function, making metabolomics a valuable reflection of a cell's phenotype. In the OMICs era, metabolomics analysis of cells brings numerous advantages over existing methods, propelling cell metabolomics as an emerging field with vast potential for investigating metabolic pathways and their perturbation in pathophysiological conditions. This review article aims to look into recent developments in applying metabolomics for characterizing and interpreting the cellular metabolome in thyroid cancer cell lines, exploring their unique metabolic characteristics. Understanding the metabolic alterations in tumor cells can lead to the identification of critical nodes in the metabolic network that could be targeted for therapeutic intervention.

Keywords:  Cell line models; Metabolic pathways; Metabolism; Metabolomics; Thyroid cancer

DOI:  https://doi.org/10.1016/j.yexcr.2024.113936
Antioxidants (Basel). 2024 Jan 02. pii: 70. [Epub ahead of print]13(1):

The Multifaceted Roles of NRF2 in Cancer: Friend or Foe?

Christophe Glorieux, Cinthya Enríquez, Constanza González, Gabriela Aguirre-Martínez, Pedro Buc Calderon.

  Physiological concentrations of reactive oxygen species (ROS) play vital roles in various normal cellular processes, whereas excessive ROS generation is central to disease pathogenesis. The nuclear factor erythroid 2-related factor 2 (NRF2) is a critical transcription factor that regulates the cellular antioxidant systems in response to oxidative stress by governing the expression of genes encoding antioxidant enzymes that shield cells from diverse oxidative alterations. NRF2 and its negative regulator Kelch-like ECH-associated protein 1 (KEAP1) have been the focus of numerous investigations in elucidating whether NRF2 suppresses tumor promotion or conversely exerts pro-oncogenic effects. NRF2 has been found to participate in various pathological processes, including dysregulated cell proliferation, metabolic remodeling, and resistance to apoptosis. Herein, this review article will examine the intriguing role of phase separation in activating the NRF2 transcriptional activity and explore the NRF2 dual impacts on tumor immunology, cancer stem cells, metastasis, and long non-coding RNAs (LncRNAs). Taken together, this review aims to discuss the NRF2 multifaceted roles in both cancer prevention and promotion while also addressing the advantages, disadvantages, and limitations associated with modulating NRF2 therapeutically in cancer treatment.

Keywords:  LncRNA; NRF2; NRF2 activators; NRF2 inhibitors; cancer; metabolism; metastasis; natural compounds; phase separation; tumor immunology

DOI:  https://doi.org/10.3390/antiox13010070
J Cancer Res Ther. 2024 Jan 22.

Oral glutamine: Is there a role in the amelioration of radiation-induced mucositis? A prospective case-control study at a tertiary care centre in North India.

Kaneez Fatima, Asifa Andleeb, Shahida Nasreen, Mushtaq A Sofi, Arshad M Najmi, Sumyra K Qadri, Rubyiya Ryhan, Shagufta Roohi, Fir Afroz, Nazir A Khan.

BACKGROUND: The most frequently occurring painful and dose-limiting side effect of radiation therapy (RT) to the head and neck region is oral mucositis (OM). Several studies demonstrated that glutamine may reduce the severity and the duration of OM significantly during RT and chemo-radiotherapy in patients with head and neck cancer (HNC).MATERIALS AND METHODS: Between January 2021 and August 2022, a prospective single institutional case-control study compared the efficacy and safety of oral glutamine on radiation-induced mucositis in patients with HNC. Of 60 biopsy-proven patients with HNC, 30 patients in the study arm received oral glutamine suspension (10 g in 500 mL of water) orally once daily, 2 hours before RT, receiving definitive or adjuvant RT and chemo-radiotherapy, while as 30 patients in the control arm received placebo with the same dose and schedule (n = 30 in the study arm and n = 30 in the control arm).
RESULTS AND ANALYSIS: A total of 27 (90%) in the glutamine arm and 28 (93.33%) patients in the control arm developed mucositis. Grade 3 mucositis (13.33%) and Grade 4 mucositis (6.66%), respectively, were significantly less (P = .040 and P = .004) in the glutamine arm. The mean duration of grade 3 and grade 4 mucositis was significantly less in the glutamine arm (8.94 days in the study arm vs. 14.54 in the control arm; P = .0001). The mean time of onset of OM was significantly delayed in the glutamine arm in comparison to the control arm with P < .001.
CONCLUSION: Glutamine delays the onset of OM and decreases the severity of OM in patients of HNC receiving RT with or without chemotherapy.

DOI: https://doi.org/10.4103/jcrt.jcrt_2742_22
Int J Biol Macromol. 2024 Jan 23. pii: S0141-8130(24)00449-5. [Epub ahead of print]260(Pt 2): 129646

Comprehensive review of amino acid transporters as therapeutic targets.

Ran Xia, Hai-Feng Peng, Xing Zhang, Hong-Sheng Zhang.

  The solute carrier (SLC) family, with more than 400 membrane-bound proteins, facilitates the transport of a wide array of substrates such as nutrients, ions, metabolites, and drugs across biological membranes. Amino acid transporters (AATs) are membrane transport proteins that mediate transfer of amino acids into and out of cells or cellular organelles. AATs participate in many important physiological functions including nutrient supply, metabolic transformation, energy homeostasis, redox regulation, and neurological regulation. Several AATs have been found to significantly impact the progression of human malignancies, and dysregulation of AATs results in metabolic reprogramming affecting tumor growth and progression. However, current clinical therapies that directly target AATs have not been developed. The purpose of this review is to highlight the structural and functional diversity of AATs, the molecular mechanisms in human diseases such as tumors, kidney diseases, and emerging therapeutic strategies for targeting AATs.

Keywords:  SLC transporter; amino acid transporter; cancer therapy; targeted therapy

DOI:  https://doi.org/10.1016/j.ijbiomac.2024.129646
Int J Mol Sci. 2024 Jan 16. pii: 1097. [Epub ahead of print]25(2):

Glutathione Reductase Expression and Its Prognostic Significance in Colon Cancer.

Marlena Brzozowa-Zasada, Adam Piecuch, Karolina Bajdak-Rusinek, Marek Michalski, Olesya Klymenko, Natalia Matysiak, Kamil Janelt, Zenon Czuba.

  Maintaining a balanced redox state within cells is crucial for the sustenance of life. The process involves continuous cytosolic disulfide reduction reactions to restore oxidized proteins to their reduced thiol forms. There are two main cellular antioxidant pathways-the thioredoxin (Trx) and glutathione (GSH)/glutaredoxin (Grx) systems. In the GSH/Grx system, glutathione reductase (GR; GSR) catalyses the reduction of GSH disulfide (GSSG) to its sulfhydryl form (GSH), which can then further reduce oxidized Grxs. GR is an essential enzyme that helps in maintaining the supply of reduced glutathione-GSH, which is a significant reducing thiol found in most cells and known for its antioxidant properties. Therefore, it can have a significant impact on cancer development. To investigate this further, we performed an immunohistochemical analysis of GR protein expression in colon adenocarcinoma samples collected from patients with primary colon adenocarcinoma (stage I and II) and patients with metastasis to regional lymph nodes (stage III). The results of our study revealed a significant relationship between the immunohistochemical expression of GR and tumour histological grade, depth of invasion, regional lymph node involvement, staging, and PCNA immunohistochemical expression. It was found that 95% of patients with stage I had low levels of GR expression, whereas 89% of patients with stage III had high levels of immunohistochemical expression. A high level of expression was also detected in the patients with stage II of the disease, where almost 63% were characterized by a high expression of GR. The Western blot method revealed that the highest level of expression was found in the LS 174T cell line, which corresponds to stage II. The results of our study indicate that the immunohistochemical expression of GR may act as an independent prognostic factor associated with colon adenocarcinoma patients' prognosis.

Keywords:  ELISA; Western blot; chromosomal instability (CIN); colorectal cancer; glutaredoxin; glutathione system (GSH); oxidative stress; prognostic factor; redox homeostasis

DOI:  https://doi.org/10.3390/ijms25021097