bims-glucam 2024-03-31 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024‒03‒31
sixteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Enhancing Leukemia Treatment: The Role of Combined Therapies Based on Amino Acid Starvation.
Glutamine antagonists may KEAP lung cancer in check.
Elucidation and Regulation of Tyrosine Kinase Inhibitor Resistance in Renal Cell Carcinoma Cells from the Perspective of Glutamine Metabolism.
Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer.
Complex I activity in hypoxia: implications for oncometabolism.
The Accumulation of Phenyllactic Acid Impairs Host Glutamine Metabolism and Inhibits African Swine Fever Virus Replication: A Novel Target for the Development of Anti-ASFV Drugs.
ERK5 Interacts with Mitochondrial Glutaminase and Regulates Its Expression.
Targeting metabolic adaptive responses induced by glucose starvation inhibits cell proliferation and enhances cell death in osimertinib-resistant non-small cell lung cancer (NSCLC) cell lines.
The pleiotropic functions of reactive oxygen species in cancer.
The Molecular Mechanisms behind Advanced Breast Cancer Metabolism: Warburg Effect, OXPHOS, and Calcium.
Standard Doses of Cholecalciferol Reduce Glucose and Increase Glutamine in Obesity-Related Hypertension: Results of a Randomized Trial.
Targeting the Warburg Effect in Cancer: Where Do We Stand?
Enhancing Antibody-Specific Productivity: Unraveling the Impact of XBP1s Overexpression and Glutamine Availability in SP2/0 Cells.
Tricarboxylic Acid Cycle Intermediates and Individual Ageing.
Induction of Oxidative Stress and Ferroptosis in Triple-Negative Breast Cancer Cells by Niclosamide via Blockade of the Function and Expression of SLC38A5 and SLC7A11.
Glutamine Promotes Porcine Intestinal Epithelial Cell Proliferation through the Wnt/β-Catenin Pathway.

Cancers (Basel). 2024 Mar 16. pii: 1171. [Epub ahead of print]16(6):

Enhancing Leukemia Treatment: The Role of Combined Therapies Based on Amino Acid Starvation.

Can Chen, Ji Zhang.

  Cancer cells demand amino acids beyond their usage as "building blocks" for protein synthesis. As a result, targeting amino acid acquisition and utilization has emerged as a pivotal strategy in cancer treatment. In the setting of leukemia therapy, compelling examples of targeting amino acid metabolism exist at both pre-clinical and clinical stages. This review focuses on summarizing novel insights into the metabolism of glutamine, asparagine, arginine, and tryptophan in leukemias, and providing a comprehensive discussion of perturbing their metabolism to improve the therapeutic outcomes. Certain amino acids, such as glutamine, play a vital role in the energy metabolism of cancer cells and the maintenance of redox balance, while others, such as arginine and tryptophan, contribute significantly to the immune microenvironment. Therefore, assessing the efficacy of targeting amino acid metabolism requires comprehensive strategies. Combining traditional chemotherapeutics with novel strategies to perturb amino acid metabolism is another way to improve the outcome in leukemia patients via overcoming chemo-resistance or promoting immunotherapy. In this review, we also discuss several ongoing or complete clinical trials, in which targeting amino acid metabolism is combined with other chemotherapeutics in treating leukemia.

Keywords:  GCN2; amino acid starvation; combination therapy; immunosuppression; leukemia

DOI:  https://doi.org/10.3390/cancers16061171
Sci Adv. 2024 Mar 29. 10(13): eado7808

Glutamine antagonists may KEAP lung cancer in check.

Eliot B Blatt, Ralph J DeBerardinis.

The glutamine antagonist DRP-104 blocks purine synthesis and combines with checkpoint inhibitors to promote antitumor immunity in KEAP1/NRF2-mutant lung cancers.

DOI: https://doi.org/10.1126/sciadv.ado7808
Metabolites. 2024 Mar 19. pii: 170. [Epub ahead of print]14(3):

Elucidation and Regulation of Tyrosine Kinase Inhibitor Resistance in Renal Cell Carcinoma Cells from the Perspective of Glutamine Metabolism.

Kento Morozumi, Yoshihide Kawasaki, Tomonori Sato, Masamitsu Maekawa, Shinya Takasaki, Shuichi Shimada, Takanari Sakai, Shinichi Yamashita, Nariyasu Mano, Akihiro Ito.

  Tyrosine kinase inhibitors (TKIs) play a crucial role in the treatment of advanced renal cell carcinoma (RCC). However, there is a lack of useful biomarkers for assessing treatment efficacy. Through urinary metabolite analysis, we identified the metabolites and pathways involved in TKI resistance and elucidated the mechanism of TKI resistance. To verify the involvement of the identified metabolites obtained from urine metabolite analysis, we established sunitinib-resistant RCC cells and elucidated the antitumor effects of controlling the identified metabolic pathways in sunitinib-resistant RCC cells. Through the analysis of VEGFR signaling, we aimed to explore the mechanisms underlying the antitumor effects of metabolic control. Glutamine metabolism has emerged as a significant pathway in urinary metabolite analyses. In vitro and in vivo studies have revealed the antitumor effects of sunitinib-resistant RCC cells via knockdown of glutamine transporters. Furthermore, this antitumor effect is mediated by the control of VEGFR signaling via PTEN. Our findings highlight the involvement of glutamine metabolism in the prognosis and sunitinib resistance in patients with advanced RCC. Additionally, the regulating glutamine metabolism resulted in antitumor effects through sunitinib re-sensitivity in sunitinib-resistant RCC. Our results are expected to contribute to the more effective utilization of TKIs with further improvements in prognosis through current drug therapies.

Keywords:  PTEN; TKI resistance; VEGF signaling; VEGFR; glutamine metabolism; renal cell carcinoma

DOI:  https://doi.org/10.3390/metabo14030170
Sci Adv. 2024 Mar 29. 10(13): eadm9859

Glutamine antagonist DRP-104 suppresses tumor growth and enhances response to checkpoint blockade in KEAP1 mutant lung cancer.

Ray Pillai, Sarah E LeBoeuf, Yuan Hao, Connie New, Jenna L E Blum, Ali Rashidfarrokhi, Shih Ming Huang, Christian Bahamon, Warren L Wu, Burcu Karadal-Ferrena, Alberto Herrera, Ellie Ivanova, Michael Cross, Jozef P Bossowski, Hongyu Ding, Makiko Hayashi, Sahith Rajalingam, Triantafyllia Karakousi, Volkan I Sayin, Kamal M Khanna, Kwok-Kin Wong, Robert Wild, Aristotelis Tsirigos, John T Poirier, Charles M Rudin, Shawn M Davidson, Sergei B Koralov, Thales Papagiannakopoulos.

Loss-of-function mutations in KEAP1 frequently occur in lung cancer and are associated with poor prognosis and resistance to standard of care treatment, highlighting the need for the development of targeted therapies. We previously showed that KEAP1 mutant tumors consume glutamine to support the metabolic rewiring associated with NRF2-dependent antioxidant production. Here, using preclinical patient-derived xenograft models and antigenic orthotopic lung cancer models, we show that the glutamine antagonist prodrug DRP-104 impairs the growth of KEAP1 mutant tumors. We find that DRP-104 suppresses KEAP1 mutant tumors by inhibiting glutamine-dependent nucleotide synthesis and promoting antitumor T cell responses. Using multimodal single-cell sequencing and ex vivo functional assays, we demonstrate that DRP-104 reverses T cell exhaustion, decreases Tregs, and enhances the function of CD4 and CD8 T cells, culminating in an improved response to anti-PD1 therapy. Our preclinical findings provide compelling evidence that DRP-104, currently in clinical trials, offers a promising therapeutic approach for treating patients with KEAP1 mutant lung cancer.

DOI: https://doi.org/10.1126/sciadv.adm9859
Biochem Soc Trans. 2024 Mar 25. pii: BST20230189. [Epub ahead of print]

Complex I activity in hypoxia: implications for oncometabolism.

Christos Chinopoulos.

  Certain cancer cells within solid tumors experience hypoxia, rendering them incapable of oxidative phosphorylation (OXPHOS). Despite this oxygen deficiency, these cells exhibit biochemical pathway activity that relies on NAD+. This mini-review scrutinizes the persistent, residual Complex I activity that oxidizes NADH in the absence of oxygen as the electron acceptor. The resulting NAD+ assumes a pivotal role in fueling the α-ketoglutarate dehydrogenase complex, a critical component in the oxidative decarboxylation branch of glutaminolysis - a hallmark oncometabolic pathway. The proposition is that through glutamine catabolism, high-energy phosphate intermediates are produced via substrate-level phosphorylation in the mitochondrial matrix substantiated by succinyl-CoA ligase, partially compensating for an OXPHOS deficiency. These insights provide a rationale for exploring Complex I inhibitors in cancer treatment, even when OXPHOS functionality is already compromised.

Keywords:  OXPHOS; cancer; hypoxia; mitochondria; mtSLP

DOI:  https://doi.org/10.1042/BST20230189
Viruses. 2024 Mar 13. pii: 449. [Epub ahead of print]16(3):

The Accumulation of Phenyllactic Acid Impairs Host Glutamine Metabolism and Inhibits African Swine Fever Virus Replication: A Novel Target for the Development of Anti-ASFV Drugs.

Junfei Dai, Xusheng Ma, Ashenafi Kiros Wubshet, Qian Li, Xiaofen Shang, Zhikuan Luo, Jianan Liu, Zhiyu Li, Mingxia Li, Yujie Song, Lijun Guo, Jie Zhang, Haixue Zheng.

  African swine fever (ASF) is a highly contagious and hemorrhagic disease caused by infection with the African swine fever virus (ASFV), resulting in a mortality rate of up to 100%. Currently, there are no effective treatments and commercially available vaccines for ASF. Therefore, it is crucial to identify biochemicals derived from host cells that can impede ASFV replication, with the aim of preventing and controlling ASF. The ASFV is an acellular organism that promotes self-replication by hijacking the metabolic machinery and biochemical resources of host cells. ASFV specifically alters the utilization of glucose and glutamine, which are the primary metabolic sources in mammalian cells. This study aimed to investigate the impact of glucose and glutamine metabolic dynamics on the rate of ASFV replication. Our findings demonstrate that ASFV infection favors using glutamine as a metabolic fuel to facilitate self-replication. ASFV replication can be substantially inhibited by blocking glutamine metabolism. The metabolomics analysis of the host cell after late-stage ASFV infection revealed a significant disruption of normal glutamine metabolic pathways due to the abundant expression of PLA (phenyllactic acid). Pretreatment with PLA also inhibited ASFV proliferation and glutamine consumption following infection. The metabolomic analysis also showed that PLA pretreatment greatly slowed down the metabolism of amino acids and nucleotides that depend on glutamine. The depletion of these building blocks directly hindered the replication of ASFV by decreasing the biosynthetic precursors produced during the replication of ASFV's progeny virus. These findings provide valuable insight into the possibility of pursuing the development of antiviral drugs against ASFV that selectively target metabolic pathways.

Keywords:  ASFV; glutamine; inhibition; metabolics; phenyllactic acid

DOI:  https://doi.org/10.3390/v16030449
Int J Mol Sci. 2024 Mar 14. pii: 3273. [Epub ahead of print]25(6):

ERK5 Interacts with Mitochondrial Glutaminase and Regulates Its Expression.

Yolanda María Guillén-Pérez, María Jesús Ortiz-Ruiz, Javier Márquez, Atanasio Pandiella, Azucena Esparís-Ogando.

  Many of the biological processes of the cell, from its structure to signal transduction, involve protein-protein interactions. On this basis, our aim was to identify cellular proteins that interact with ERK5, a serine/threonine protein kinase with a key role in tumor genesis and progression and a promising therapeutic target in many tumor types. Using affinity chromatography, immunoprecipitation, and mass spectrometry techniques, we unveiled an interaction between ERK5 and the mitochondrial glutaminase GLS in pancreatic tumor cells. Subsequent co-immunoprecipitation and immunofluorescence studies supported this interaction in breast and lung tumor cells as well. Genetic approaches using RNA interference techniques and CRISPR/Cas9 technology demonstrated that the loss of ERK5 function led to increased protein levels of GLS isoforms (KGA/GAC) and a concomitant increase in their activity in tumor cells. It is well known that the tumor cell reprograms its intermediary metabolism to meet its increased metabolic needs. In this sense, mitochondrial GLS is involved in the first step of glutamine catabolism, one of the main energy sources in the context of cancer. Our data suggest that ERK5 contributes to the regulation of tumor cell energy metabolism via glutaminolysis.

Keywords:  ERK5; GLS isoforms; cancer therapy; energy metabolism; glutaminase; mitochondria; proteomics

DOI:  https://doi.org/10.3390/ijms25063273
Biochem Pharmacol. 2024 Mar 24. pii: S0006-2952(24)00144-8. [Epub ahead of print] 116161

Targeting metabolic adaptive responses induced by glucose starvation inhibits cell proliferation and enhances cell death in osimertinib-resistant non-small cell lung cancer (NSCLC) cell lines.

Kamal Eltayeb, Roberta Alfieri, Claudia Fumarola, Mara Bonelli, Maricla Galetti, Andrea Cavazzoni, Graziana Digiacomo, Francesca Galvani, Federica Vacondio, Alessio Lodola, Marco Mor, Roberta Minari, Marcello Tiseo, Silvia La Monica, Pier Giorgio Petronini.

  Osimertinib, a tyrosine kinase inhibitor targeting mutant EGFR, has received approval for initial treatment in patients with Non-Small Cell Lung Cancer (NSCLC). While effective in both first- and second-line treatments, patients eventually develop acquired resistance. Metabolic reprogramming represents a strategy through which cancer cells may resist and adapt to the selective pressure exerted by the drug. In the current study, we investigated the metabolic adaptations associated with osimertinib-resistance in NSCLC cells under low glucose culture conditions. We demonstrated that, unlike osimertinib-sensitive cells, osimertinib-resistant cells were able to survive under low glucose conditions by increasing the rate of glucose and glutamine uptake and by shifting towards mitochondrial metabolism. Inhibiting glucose/pyruvate contribution to mitochondrial respiration, glutamine deamination to glutamate, and oxidative phosphorylation decreased the proliferation and survival abilities of osimertinib-resistant cells to glucose starvation. Our findings underscore the remarkable adaptability of osimertinib-resistant NSCLC cells in a low glucose environment and highlight the pivotal role of mitochondrial metabolism in mediating this adaptation. Targeting the metabolic adaptive responses triggered by glucose shortage emerges as a promising strategy, effectively inhibiting cell proliferation and promoting cell death in osimertinib-resistant cells.

Keywords:  EGFR; Glucose; Metabolism; NSCLC; Osimertinib; Resistance

DOI:  https://doi.org/10.1016/j.bcp.2024.116161
Nat Cancer. 2024 Mar;5(3): 384-399

The pleiotropic functions of reactive oxygen species in cancer.

Katherine Wu, Ahmed Ezat El Zowalaty, Volkan I Sayin, Thales Papagiannakopoulos.

Cellular redox homeostasis is an essential, dynamic process that ensures the balance between reducing and oxidizing reactions within cells and thus has implications across all areas of biology. Changes in levels of reactive oxygen species can disrupt redox homeostasis, leading to oxidative or reductive stress that contributes to the pathogenesis of many malignancies, including cancer. From transformation and tumor initiation to metastatic dissemination, increasing reactive oxygen species in cancer cells can paradoxically promote or suppress the tumorigenic process, depending on the extent of redox stress, its spatiotemporal characteristics and the tumor microenvironment. Here we review how redox regulation influences tumorigenesis, highlighting therapeutic opportunities enabled by redox-related alterations in cancer cells.

DOI: https://doi.org/10.1038/s43018-024-00738-9
Front Biosci (Landmark Ed). 2024 Mar 13. 29(3): 99

The Molecular Mechanisms behind Advanced Breast Cancer Metabolism: Warburg Effect, OXPHOS, and Calcium.

Erna Mitaishvili, Hanna Feinsod, Zachary David, Jessica Shpigel, Chelsea Fernandez, Moira Sauane, Columba de la Parra.

  Altered metabolism represents a fundamental difference between cancer cells and normal cells. Cancer cells have a unique ability to reprogram their metabolism by deviating their reliance from primarily oxidative phosphorylation (OXPHOS) to glycolysis, in order to support their survival. This metabolic phenotype is referred to as the "Warburg effect" and is associated with an increase in glucose uptake, and a diversion of glycolytic intermediates to alternative pathways that support anabolic processes. These processes include synthesis of nucleic acids, lipids, and proteins, necessary for the rapidly dividing cancer cells, sustaining their growth, proliferation, and capacity for successful metastasis. Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer, with the poorest patient outcome due to its high rate of metastasis. TNBC is characterized by elevated glycolysis and in certain instances, low OXPHOS. This metabolic dysregulation is linked to chemotherapeutic resistance in TNBC research models and patient samples. There is more than a single mechanism by which this metabolic switch occurs and here, we review the current knowledge of relevant molecular mechanisms involved in advanced breast cancer metabolism, focusing on TNBC. These mechanisms include the Warburg effect, glycolytic adaptations, microRNA regulation, mitochondrial involvement, mitochondrial calcium signaling, and a more recent player in metabolic regulation, JAK/STAT signaling. In addition, we explore some of the drugs and compounds targeting cancer metabolic reprogramming. Research on these mechanisms is highly promising and could ultimately offer new opportunities for the development of innovative therapies to treat advanced breast cancer characterized by dysregulated metabolism.

Keywords:  JAK/STAT; OXPHOS; ROS; TNBC; Warburg effect; glycolysis; hexokinase; metabolic reprogramming; miRNAs; mitochondrial Ca2+

DOI:  https://doi.org/10.31083/j.fbl2903099
Int J Mol Sci. 2024 Mar 18. pii: 3416. [Epub ahead of print]25(6):

Standard Doses of Cholecalciferol Reduce Glucose and Increase Glutamine in Obesity-Related Hypertension: Results of a Randomized Trial.

Catarina Santos, Rui Carvalho, Ana Mafalda Fonseca, Miguel Castelo Branco, Marco Alves, Ivana Jarak.

  In arterial hypertension, the dysregulation of several metabolic pathways is closely associated with chronic immune imbalance and inflammation progression. With time, these disturbances lead to the development of progressive disease and end-organ involvement. However, the influence of cholecalciferol on metabolic pathways as a possible mechanism of its immunomodulatory activity in obesity-related hypertension is not known. In a phase 2, randomized, single-center, 24-week trial, we evaluated, as a secondary outcome, the serum metabolome of 36 age- and gender-matched adults with obesity-related hypertension and vitamin D deficiency, before and after supplementation with cholecalciferol therapy along with routine medication. The defined endpoint was the assessment of circulating metabolites using a nuclear magnetic resonance-based metabolomics approach. Univariate and multivariate analyses were used to evaluate the systemic metabolic alterations caused by cholecalciferol. In comparison with normotensive controls, hypertensive patients presented overall decreased expression of several amino acids (p < 0.05), including amino acids with ketogenic and glucogenic properties as well as aromatic amino acids. Following cholecalciferol supplementation, increases were observed in glutamine (p < 0.001) and histidine levels (p < 0.05), with several other amino acids remaining unaffected. Glucose (p < 0.05) and acetate (p < 0.05) decreased after 24 weeks in the group taking the supplement, and changes in the saturation of fatty acids (p < 0.05) were also observed, suggesting a role of liposoluble vitamin D in lipid metabolism. Long-term cholecalciferol supplementation in chronically obese and overweight hypertensives induced changes in the blood serum metabolome, which reflected systemic metabolism and may have fostered a new microenvironment for cell proliferation and biology. Of note, the increased availability of glutamine may be relevant for the proliferation of different T-cell subsets.

Keywords:  glucose; glutamine; hypertension; metabolites; obesity; vitamin D

DOI:  https://doi.org/10.3390/ijms25063416
Int J Mol Sci. 2024 Mar 08. pii: 3142. [Epub ahead of print]25(6):

Targeting the Warburg Effect in Cancer: Where Do We Stand?

Ignasi Barba, Laura Carrillo-Bosch, Joan Seoane.

  The Warburg effect, characterized by the preferential conversion of glucose to lactate even in the presence of oxygen and functional mitochondria, is a prominent metabolic hallmark of cancer cells and has emerged as a promising therapeutic target for cancer therapy. Elevated lactate levels and acidic pH within the tumor microenvironment (TME) resulting from glycolytic profoundly impact various cellular populations, including macrophage reprogramming and impairment of T-cell functionality. Altogether, the Warburg effect has been shown to promote tumor progression and immunosuppression through multiple mechanisms. This review provides an overview of the current understanding of the Warburg effect in cancer and its implications. We summarize recent pharmacological strategies aimed at targeting glycolytic enzymes, highlighting the challenges encountered in achieving therapeutic efficacy. Additionally, we examine the utility of the Warburg effect as an early diagnostic tool. Finally, we discuss the multifaceted roles of lactate within the TME, emphasizing its potential as a therapeutic target to disrupt metabolic interactions between tumor and immune cells, thereby enhancing anti-tumor immunity.

Keywords:  Warburg effect; aerobic glycolysis; immunomodulation; tumor metabolism; tumor microenvironment

DOI:  https://doi.org/10.3390/ijms25063142
Bioengineering (Basel). 2024 Feb 21. pii: 201. [Epub ahead of print]11(3):

Enhancing Antibody-Specific Productivity: Unraveling the Impact of XBP1s Overexpression and Glutamine Availability in SP2/0 Cells.

Priscilla González-Pereira, Ryan Trinh, Alex Vasuthasawat, Angelo Bartsch-Jiménez, Constanza Nuñez-Soto, Claudia Altamirano.

  Augmentation of glycoprotein synthesis requirements induces endoplasmic reticulum (ER) stress, activating the unfolded protein response (UPR) and triggering unconventional XBP1 splicing. As a result, XBP1s orchestrates the expression of essential genes to reduce stress and restore homeostasis. When this mechanism fails, chronic stress may lead to apoptosis, which is thought to be associated with exceeding a threshold in XBP1s levels. Glycoprotein assembly is also affected by glutamine (Gln) availability, limiting nucleotide sugars (NS), and preventing compliance with the increased demands. In contrast, increased Gln intake synthesizes ammonia as a by-product, potentially reaching toxic levels. IgA2m(1)-producer mouse myeloma cells (SP2/0) were used as the cellular mammalian model. We explored how IgA2m(1)-specific productivity (qIgA2m(1)) is affected by (i) overexpression of human XBP1s (h-XBP1s) levels and (ii) Gln availability, evaluating the kinetic behavior in batch cultures. The study revealed a two and a five-fold increase in qIgA2m(1) when lower and higher levels of XBP1s were expressed, respectively. High h-XBP1s overexpression mitigated not only ammonia but also lactate accumulation. Moreover, XBP1s overexpressor showed resilience to hydrodynamic stress in serum-free environments. These findings suggest a potential application of h-XBP1s overexpression as a feasible and cost-effective strategy for bioprocess scalability.

Keywords:  IgA; SP2/0 cells; XBP1s; ammonia; antibody; glutamine (Gln); lactate; productivity; unfolded protein response

DOI:  https://doi.org/10.3390/bioengineering11030201
Biomolecules. 2024 Feb 22. pii: 260. [Epub ahead of print]14(3):

Tricarboxylic Acid Cycle Intermediates and Individual Ageing.

Natalia Kurhaluk.

  Anti-ageing biology and medicine programmes are a focus of genetics, molecular biology, immunology, endocrinology, nutrition, and therapy. This paper discusses metabolic therapies aimed at prolonging longevity and/or health. Individual components of these effects are postulated to be related to the energy supply by tricarboxylic acid (TCA) cycle intermediates and free radical production processes. This article presents several theories of ageing and clinical descriptions of the top markers of ageing, which define ageing in different categories; additionally, their interactions with age-related changes and diseases related to α-ketoglutarate (AKG) and succinate SC formation and metabolism in pathological states are explained. This review describes convincingly the differences in the mitochondrial characteristics of energy metabolism in animals, with different levels (high and low) of physiological reactivity of functional systems related to the state of different regulatory systems providing oxygen-dependent processes. Much attention is given to the crucial role of AKG and SC in the energy metabolism in cells related to amino acid synthesis, epigenetic regulation, cell stemness, and differentiation, as well as metabolism associated with the development of pathological conditions and, in particular, cancer cells. Another goal was to address the issue of ageing in terms of individual characteristics related to physiological reactivity. This review also demonstrated the role of the Krebs cycle as a key component of cellular energy and ageing, which is closely associated with the development of various age-related pathologies, such as cancer, type 2 diabetes, and cardiovascular or neurodegenerative diseases where the mTOR pathway plays a key role. This article provides postulates of postischaemic phenomena in an ageing organism and demonstrates the dependence of accelerated ageing and age-related pathology on the levels of AKG and SC in studies on different species (roundworm Caenorhabditis elegans, Drosophila, mice, and humans used as models). The findings suggest that this approach may also be useful to show that Krebs cycle metabolites may be involved in age-related abnormalities of the mitochondrial metabolism and may thus induce epigenetic reprogramming that contributes to the senile phenotype and degenerative diseases. The metabolism of these compounds is particularly important when considering ageing mechanisms connected with different levels of initial physiological reactivity and able to initiate individual programmed ageing, depending on the intensity of oxygen consumption, metabolic peculiarities, and behavioural reactions.

Keywords:  ageing mechanisms; anti-ageing therapy; bioenergetic mechanisms of ageing; individual ageing processes; individual physiological reactivity; tricarboxylic acid cycle intermediates

DOI:  https://doi.org/10.3390/biom14030260
Antioxidants (Basel). 2024 Feb 27. pii: 291. [Epub ahead of print]13(3):

Induction of Oxidative Stress and Ferroptosis in Triple-Negative Breast Cancer Cells by Niclosamide via Blockade of the Function and Expression of SLC38A5 and SLC7A11.

Marilyn Mathew, Sathish Sivaprakasam, Gunadharini Dharmalingam-Nandagopal, Souad R Sennoune, Nhi T Nguyen, Valeria Jaramillo-Martinez, Yangzom D Bhutia, Vadivel Ganapathy.

  The amino acid transporters SLC38A5 and SLC7A11 are upregulated in triple-negative breast cancer (TNBC). SLC38A5 transports glutamine, methionine, glycine and serine, and therefore activates mTOR signaling and induces epigenetic modifications. SLC7A11 transports cystine and increases the cellular levels of glutathione, which protects against oxidative stress and lipid peroxidation via glutathione peroxidase, a seleno (Se)-enzyme. The primary source of Se is dietary Se-methionine (Se-Met). Since SLC38A5 transports methionine, we examined its role in Se-Met uptake in TNBC cells. We found that SLC38A5 interacts with methionine and Se-Met with comparable affinity. We also examined the influence of Se-Met on Nrf2 in TNBC cells. Se-Met activated Nrf2 and induced the expression of Nrf2-target genes, including SLC7A11. Our previous work discovered niclosamide, an antiparasitic drug, as a potent inhibitor of SLC38A5. Here, we found SLC7A11 to be inhibited by niclosamide with an IC50 value in the range of 0.1-0.2 μM. In addition to the direct inhibition of SLC38A5 and SLC7A11, the pretreatment of TNBC cells with niclosamide reduced the expression of both transporters. Niclosamide decreased the glutathione levels, inhibited proliferation, suppressed GPX4 expression, increased lipid peroxidation, and induced ferroptosis in TNBC cells. It also significantly reduced the growth of the TNBC cell line MB231 in mouse xenografts.

Keywords:  Nrf2; SLC38A5; SLC7A11; TNBC cells; ferroptosis; glutathione; glutathione peroxidase; lipid peroxidation; niclosamide; seleno-methionine

DOI:  https://doi.org/10.3390/antiox13030291
J Agric Food Chem. 2024 Mar 25.

Glutamine Promotes Porcine Intestinal Epithelial Cell Proliferation through the Wnt/β-Catenin Pathway.

Yong-Xia Fang, En-Qing Lu, Yu-Jie Cheng, E Xu, Min Zhu, Xiang Chen.

  Glutamine (Gln) is a critical nutrient required by neonatal mammals for intestinal growth, especially for newborn piglets. However, the mechanisms underlying the role of Gln in porcine intestinal epithelium development are not fully understood. The objective of the current study was to explore the possible signaling pathway involved in the promotion of porcine intestinal epithelial cell (IPEC-J2) proliferation by Gln. The results showed that 1 mM Gln promoted IPEC-J2 cell proliferation, and tandem mass tag proteomics revealed 973 differentially expressed proteins in Gln-treated IPEC-J2 cells, 824 of which were upregulated and 149 of which were downregulated. Moreover, gene set enrichment analysis indicated that the Wnt signaling pathway is activated by Gln treatment. Western blotting analysis further confirmed that Gln activated the Wnt/β-catenin signaling pathway. In addition, Gln increased not only cytosolic β-catenin but also nuclear β-catenin protein expression. LF3 (a β-catenin/TCF4 interaction inhibitor) assay and β-catenin knockdown demonstrated that Gln-mediated promotion of Wnt/β-catenin signaling and cell proliferation were blocked. Furthermore, the inhibition of TCF4 expression suppressed Gln-induced cell proliferation. These findings further confirmed that Wnt/β-catenin signaling is involved in the promotion of IPEC-J2 cell proliferation by Gln. Collectively, these findings demonstrated that Gln positively regulated IPEC-J2 cell proliferation through the Wnt/β-catenin pathway. These data greatly enhance the current understanding of the mechanism by which Gln regulates intestinal development.

Keywords:  TMT proteomics; Wnt/β-catenin; cell proliferation; glutamine; porcine intestinal epithelial cells

DOI:  https://doi.org/10.1021/acs.jafc.3c08701