bims-glucam 2024-02-25 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024‒02‒25
sixteen papers selected by
Sreeparna Banerjee, Middle East Technical University

Targeting glutamine metabolism exhibits anti-tumor effects in thyroid cancer.
CENPA promotes glutamine metabolism and tumor progression by up-regulating SLC38A1 in endometrial cancer.
Inhibiting Glutaminase Exerts Opposite Effects on Ovariectomy-Induced and Age-Related Reductions in Murine Bone Mass.
Targeting MYC at the intersection between cancer metabolism and oncoimmunology.
Metabolic Responses of Lung Adenocarcinoma Cells to Survive under Stressful Conditions Associated with Tumor Microenvironment.
Discovering the strength of immunometabolism in cancer therapy: Employing metabolic pathways to enhance immune responses.
Exploring Amino Acid Transporters as Therapeutic Targets for Cancer: An Examination of Inhibitor Structures, Selectivity Issues, and Discovery Approaches.
Fumarate induces LncRNA-MIR4435-2HG to regulate glutamine metabolism remodeling and promote the development of FH-deficient renal cell carcinoma.
Editorial: Immunometabolic crosstalk during viral infection.
Metabolic basis of cardiac dysfunction in cancer patients.
Evolution and variation in amide aminoacyl-tRNA synthesis.
Influence of glutamine metabolism on diabetes Development:A scientometric review.
OCT4 Expression in Gliomas Is Dependent on Cell Metabolism.
Cancer resistance and metastasis are maintained through oxidative phosphorylation.
Energy Metabolites and Indicative Significance of α-Ketoglutarate and α-Ketoglutaramate in Assessing the Progression of Chronic Hepatoencephalopathy.
Glutamate Provides Cytoprotective Effect for Astrocytes Against Ischemic Insult and Promotes Astrogliosis.

J Endocrinol Invest. 2024 Feb 22.

Targeting glutamine metabolism exhibits anti-tumor effects in thyroid cancer.

G-Q Zhang, C Xi, N-T Ju, C-T Shen, Z-L Qiu, H-J Song, Q-Y Luo.

  BACKGROUND: Effective treatment for patients with advanced thyroid cancer is lacking. Metabolism reprogramming is required for cancer to undergo oncogenic transformation and rapid tumorigenic growth. Glutamine is frequently used by cancer cells for active bioenergetic and biosynthetic needs. This study aims to investigate whether targeting glutamine metabolism is a promising therapeutic strategy for thyroid cancer.METHODS: The expression of glutaminase (GLS) and glutamate dehydrogenase (GDH) in thyroid cancer tissues was evaluated by immunohistochemistry, and glutamine metabolism-related genes were assessed using real time-qPCR and western blotting. The effects of glutamine metabolism inhibitor 6-diazo-5-oxo-l-norleucine (DON) on thyroid cancer cells were determined by CCK-8, clone formation assay, Edu incorporation assay, flow cytometry, and Transwell assay. The mechanistic study was performed by real time-qPCR, western blotting, Seahorse assay, and gas chromatography-mass spectrometer assay. The effect of DON prodrug (JHU-083) on thyroid cancer in vivo was assessed using xenograft tumor models in BALB/c nude mice.
RESULTS: GLS and GDH were over-expressed in thyroid cancer tissues, and GLS expression was positively associated with lymph-node metastasis and TNM stage. The growth of thyroid cancer cells was significantly inhibited when cultured in glutamine-free medium. Targeting glutamine metabolism with DON inhibited the proliferation of thyroid cancer cells. DON treatment did not promote apoptosis, but increased the proportion of cells in the S phase, accompanied by the decreased expression of cyclin-dependent kinase 2 and cyclin A. DON treatment also significantly inhibited the migration and invasion of thyroid cancer cells by reducing the expression of N-cadherin, Vimentin, matrix metalloproteinase-2, and matrix metalloproteinase-9. Non-essential amino acids, including proline, alanine, aspartate, asparagine, and glycine, were reduced in thyroid cancer cells treated with DON, which could explain the decrease of proteins involved in migration, invasion, and cell cycle. The efficacy and safety of DON prodrug (JHU-083) for thyroid cancer treatment were verified in a mouse model. In addition to suppressing the proliferation and metastasis potential of thyroid cancer in vivo, enhanced innate immune response was also observed in JHU-083-treated xenograft tumors as a result of decreased expression of cluster of differentiation 47 and programmed cell death ligand 1.
CONCLUSIONS: Thyroid cancer exhibited enhanced glutamine metabolism, as evidenced by the glutamine dependence of thyroid cancer cells and high expression of multiple glutamine metabolism-related genes. Targeting glutamine metabolism with DON prodrug could be a promising therapeutic option for advanced thyroid cancer.

Keywords:  DON; Glutamine; Metabolism reprogramming; Thyroid cancer; Treatment

DOI:  https://doi.org/10.1007/s40618-023-02294-y
Cell Signal. 2024 Feb 20. pii: S0898-6568(24)00078-0. [Epub ahead of print]117 111110

CENPA promotes glutamine metabolism and tumor progression by up-regulating SLC38A1 in endometrial cancer.

Shuang Li, Zihui Zhang, Zhifang Li, Lian Yang, Jianfeng Liu, Yujie Liu, Yancai Liu, Yanmei Hou, Mei Mei, Yuqin Huang.

  Glutamine addiction is a significant hallmark of metabolic reprogramming in tumors and is crucial to the progression of cancer. Nevertheless, the regulatory mechanisms of glutamine metabolism in endometrial cancer (EC) remains elusive. In this research, we found that elevated expression of CENPA and solute carrier family 38 member 1 (SLC38A1) were firmly associated with worse clinical stage and unfavorable outcomes in EC patients. In addition, ectopic overexpression or silencing of CENPA could either enhance or diminish glutamine metabolism and tumor progression in EC. Mechanistically, CENPA directly regulated the transcriptional activity of the target gene, SLC38A1, leading to enhanced glutamine uptake and metabolism, thereby promoting EC progression. Notably, a prognostic model utilizing the expression levels of CENPA and SLC38A1 genes independently emerged as a prognostic factor for EC. More importantly, CENPA and SLC38A1 were significantly elevated and positively correlated, as well as indicative of poor prognosis in multiple cancers. In brief, our study confirmed that CENPA is a critical transcription factor involved in glutamine metabolism and tumor progression through modulating SLC38A1. This revelation suggests that targeting CENPA could be an appealing therapeutic approach to address pan-cancer glutamine addiction.

Keywords:  CENPA; Endometrial cancer; Glutamine; SLC38A1

DOI:  https://doi.org/10.1016/j.cellsig.2024.111110
Aging Dis. 2024 Feb 06.

Inhibiting Glutaminase Exerts Opposite Effects on Ovariectomy-Induced and Age-Related Reductions in Murine Bone Mass.

Qian Guo, Hongjian Zhao, Zijian Dong, Haozhe Cheng, Meipeng Zhu, Zhong Fang.

Recent studies have provided links between glutamine metabolism and bone remodeling, but little is known about its role in primary osteoporosis progression. We aimed to determine the effects of inhibiting glutaminase (GLS) on two types of primary osteoporosis and elucidate the related metabolism. To address this issue, age-related and ovariectomy (OVX)-induced bone loss mouse models were used to study the in vivo effects of CB-839, a potent and selective GLS inhibitor, on bone mass and bone turnover. We also studied the metabolic profile changes related with aging and GLS inhibition in primary bone marrow stromal cells (BMSC) and that related with OVX and GLS inhibition in primary bone marrow-derived monocytes (BMM). Besides, we studied the possible metabolic processes mediating GLS blockade effects during aging-impaired osteogenic differentiation and RANKL-induced osteoclast differentiation respectively via in vitro rescue experiments. We found that inhibiting GLS via CB-839 prevented OVX-induced bone loss while aggravated age-related bone loss. Further investigations showed that effects of CB-839 treatment on bone mass were associated with alterations of bone turnover. Moreover, CB-839 treatment altered metabolic profile in different orientations between BMSC of aged mice and BMM of ovariectomized mice. In addition, rescue experiments revealed that different metabolic processes mediated glutaminase blockade effects between aging-impaired osteogenic differentiation and RANKL-induced osteoclast differentiation. Taken together, our data demonstrated the different outcomes caused by CB-839 treatment between two types of osteoporosis in mice, which were tightly connected to the suppressive effects on both aging-impaired osteoblastogenesis and OVX-enhanced osteoclastogenesis mediated by different metabolic processes downstream of glutaminolysis.

DOI: https://doi.org/10.14336/AD.2024.0201
Front Immunol. 2024 ;15 1324045

Targeting MYC at the intersection between cancer metabolism and oncoimmunology.

Simran Venkatraman, Brinda Balasubramanian, Chanitra Thuwajit, Jaroslaw Meller, Rutaiwan Tohtong, Somchai Chutipongtanate.

  MYC activation is a known hallmark of cancer as it governs the gene targets involved in various facets of cancer progression. Of interest, MYC governs oncometabolism through the interactions with its partners and cofactors, as well as cancer immunity via its gene targets. Recent investigations have taken interest in characterizing these interactions through multi-Omic approaches, to better understand the vastness of the MYC network. Of the several gene targets of MYC involved in either oncometabolism or oncoimmunology, few of them overlap in function. Prominent interactions have been observed with MYC and HIF-1α, in promoting glucose and glutamine metabolism and activation of antigen presentation on regulatory T cells, and its subsequent metabolic reprogramming. This review explores existing knowledge of the role of MYC in oncometabolism and oncoimmunology. It also unravels how MYC governs transcription and influences cellular metabolism to facilitate the induction of pro- or anti-tumoral immunity. Moreover, considering the significant roles MYC holds in cancer development, the present study discusses effective direct or indirect therapeutic strategies to combat MYC-driven cancer progression.

Keywords:  MYC; cancer; immune evasion; metabolism; oncoimmunology

DOI:  https://doi.org/10.3389/fimmu.2024.1324045
Metabolites. 2024 Feb 02. pii: 103. [Epub ahead of print]14(2):

Metabolic Responses of Lung Adenocarcinoma Cells to Survive under Stressful Conditions Associated with Tumor Microenvironment.

Angeles Carlos-Reyes, Susana Romero-Garcia, Heriberto Prado-Garcia.

  Solid tumors frequently present a heterogeneous tumor microenvironment. Because tumors have the potential to proliferate quickly, the consequence is a reduction in the nutrients, a reduction in the pH (<6.8), and a hypoxic environment. Although it is often assumed that tumor clones show a similar growth rate with little variations in nutrient consumption, the present study shows how growth-specific rate (µ), the specific rates of glucose, lactate, and glutamine consumption (qS), and the specific rates of lactate and glutamate production (qP) of 2D-cultured lung tumor cells are affected by changes in their environment. We determined in lung tumor cells (A427, A549, Calu-1, and SKMES-1) the above mentioned kinetic parameters during the exponential phase under different culture conditions, varying the predominant carbon source, pH, and oxygen tension. MCF-7 cells, a breast tumor cell line that can consume lactate, and non-transformed fibroblast cells (MRC-5) were included as controls. We also analyzed how cell-cycle progression and the amino acid transporter CD98 expression were affected. Our results show that: (1) In glucose presence, μ increased, but qS Glucose and qP Lactate decreased when tumor cells were cultured under acidosis as opposed to neutral conditions; (2) most lung cancer cell lines consumed lactate under normoxia or hypoxia; (3) although qS Glutamine diminished under hypoxia or acidosis, it slightly increased in lactate presence, a finding that was associated with CD98 upregulation; and (4) under acidosis, G0/G1 arrest was induced in A427 cancer cells, although this phenomenon was significantly increased when glucose was changed by lactate as the predominant carbon-source. Hence, our results provide an understanding of metabolic responses that tumor cells develop to survive under stressful conditions, providing clues for developing promising opportunities to improve traditional cancer therapies.

Keywords:  glucose deprivation; hypoxia; lactic acidosis; specific growth rate; tumor metabolism; tumor microenvironment

DOI:  https://doi.org/10.3390/metabo14020103
Cell Biochem Funct. 2024 Mar;42(2): e3934

Discovering the strength of immunometabolism in cancer therapy: Employing metabolic pathways to enhance immune responses.

Huldani Huldani, Jitendra Malviya, Paul Rodrigues, Ahmed Hjazi, Maha Medha Deorari, Hussein Riyadh Abdul Kareem Al-Hetty, Qutaiba A Qasim, Mohammed Qasim Alasheqi, Ali Ihsan.

  Immunometabolism, which studies cellular metabolism and immune cell function, is a possible cancer treatment. Metabolic pathways regulate immune cell activation, differentiation, and effector functions, crucial to tumor identification and elimination. Immune evasion and tumor growth can result from tumor microenvironment metabolic dysregulation. These metabolic pathways can boost antitumor immunity. This overview discusses immune cell metabolism, including glycolysis, oxidative phosphorylation, amino acid, and lipid metabolism. Amino acid and lipid metabolic manipulations may improve immune cell activity and antitumor immunity. Combination therapy using immunometabolism-based strategies may enhance therapeutic efficacy. The complexity of the metabolic network, biomarker development, challenges, and future approaches are all covered, along with a summary of case studies demonstrating the effectiveness of immunometabolism-based therapy. Metabolomics, stable isotope tracing, single-cell analysis, and computational modeling are also reviewed for immunometabolism research. Personalized and combination treatments are considered. This review adds to immunometabolism expertise and sheds light on metabolic treatments' ability to boost cancer treatment immunological response. Also, in this review, we discussed the immune response in cancer treatment and altering metabolic pathways to increase the immune response against malignancies.

Keywords:  cancer; immune response; immunometabolism; metabolic pathways

DOI:  https://doi.org/10.1002/cbf.3934
Pharmaceutics. 2024 Jan 30. pii: 197. [Epub ahead of print]16(2):

Exploring Amino Acid Transporters as Therapeutic Targets for Cancer: An Examination of Inhibitor Structures, Selectivity Issues, and Discovery Approaches.

Sebastian Jakobsen, Carsten Uhd Nielsen.

  Amino acid transporters are abundant amongst the solute carrier family and have an important role in facilitating the transfer of amino acids across cell membranes. Because of their impact on cell nutrient distribution, they also appear to have an important role in the growth and development of cancer. Naturally, this has made amino acid transporters a novel target of interest for the development of new anticancer drugs. Many attempts have been made to develop inhibitors of amino acid transporters to slow down cancer cell growth, and some have even reached clinical trials. The purpose of this review is to help organize the available information on the efforts to discover amino acid transporter inhibitors by focusing on the amino acid transporters ASCT2 (SLC1A5), LAT1 (SLC7A5), xCT (SLC7A11), SNAT1 (SLC38A1), SNAT2 (SLC38A2), and PAT1 (SLC36A1). We discuss the function of the transporters, their implication in cancer, their known inhibitors, issues regarding selective inhibitors, and the efforts and strategies of discovering inhibitors. The goal is to encourage researchers to continue the search and development within the field of cancer treatment research targeting amino acid transporters.

Keywords:  ASCT2; LAT1; PAT1; SNAT1; SNAT2; amino acids; cancer; inhibitors; solute carriers; xCT

DOI:  https://doi.org/10.3390/pharmaceutics16020197
Cell Death Dis. 2024 Feb 19. 15(2): 151

Fumarate induces LncRNA-MIR4435-2HG to regulate glutamine metabolism remodeling and promote the development of FH-deficient renal cell carcinoma.

Liangsong Zhu, Yilun Hong, Ziran Zhu, Jiwei Huang, Jianfeng Wang, Ge Li, Xiaoyu Wu, Yonghui Chen, Yunze Xu, Liang Zheng, Yiran Huang, Wen Kong, Wei Xue, Jin Zhang.

Fumarate hydratase (FH) deficient renal cell carcinoma (RCC) is a type of tumor with definite metabolic disorder, but the mechanism of metabolic remodeling is still unclear. LncRNA was reported to closely correlate with cancer metabolism, however the biological role of LncRNA in the development of progression of FH-deficent RCC was not well studied either. FH-deficient RCC samples were collected in my hospital and used for RNA-sequencing and Mass spectrometry analysis. FH-deficient RCC cell line UOK262 and control pFH cells were used for in vitro experiments, including proliferation assay, transwell assay, western-blot, mass spectrometry and so on. PDX mouse model was used for further drug inhibition experiments in vivo. In this study, we analyzed the profiles of LncRNA and mRNA in FH-deficienct RCC samples, and we found that the LncRNA-MIR4435-2GH was specifically highly expressed in FH-deficient RCC compared with ccRCC. In vitro experiments demonstrated that MIR4435-2HG was regulated by Fumarate through histone demethylation, and the deletion of this gene could inhibit glutamine metabolism. RNA-pulldown experiments showed that MIR4435-2HG specifically binds to STAT1, which can transcriptionally activate GLS1. GLS1 inhibitor CB-839 could significantly suppress tumor growth in PDX tumor models. This study analyzed the molecular mechanism of MIR4435-2HG in regulating metabolic remodeling of FH-deficient RCC in clinical samples, cells and animal models by combining transcriptional and metabolic methods. We found that that GLS1 was a therapeutic target for this tumor, and MIR4435-2HG can be used as a drug sensitivity marker.

DOI: https://doi.org/10.1038/s41419-024-06510-2
Front Microbiol. 2024 ;15 1365507

Editorial: Immunometabolic crosstalk during viral infection.

Wang Guo, Hengmi Cui, Xuming Hu.



Keywords:  glucose metabolism; glutamine metabolism; immune response; immunometabolism; virus infection

DOI:  https://doi.org/10.3389/fmicb.2024.1365507
Curr Opin Cardiol. 2024 Feb 22.

Metabolic basis of cardiac dysfunction in cancer patients.

Jane C Figueiredo, Neil Adri Bhowmick, Anja Karlstaedt.

PURPOSE OF REVIEW: The relationship between metabolism and cardiovascular diseases is complex and bidirectional. Cardiac cells must adapt metabolic pathways to meet biosynthetic demands and energy requirements to maintain contractile function. During cancer, this homeostasis is challenged by the increased metabolic demands of proliferating cancer cells.RECENT FINDINGS: Tumors have a systemic metabolic impact that extends beyond the tumor microenvironment. Lipid metabolism is critical to cancer cell proliferation, metabolic adaptation, and increased cardiovascular risk. Metabolites serve as signals which provide insights for diagnosis and prognosis in cardio-oncology patients.
SUMMARY: Metabolic processes demonstrate a complex relationship between cancer cell states and cardiovascular remodeling with potential for therapeutic interventions.

DOI: https://doi.org/10.1097/HCO.0000000000001118
IUBMB Life. 2024 Feb 23.

Evolution and variation in amide aminoacyl-tRNA synthesis.

Alexander M Lewis, Trevor Fallon, Georgia A Dittemore, Kelly Sheppard.

  The amide proteogenic amino acids, asparagine and glutamine, are two of the twenty amino acids used in translation by all known life. The aminoacyl-tRNA synthetases for asparagine and glutamine, asparaginyl-tRNA synthetase and glutaminyl tRNA synthetase, evolved after the split in the last universal common ancestor of modern organisms. Before that split, life used two-step indirect pathways to synthesize asparagine and glutamine on their cognate tRNAs to form the aminoacyl-tRNA used in translation. These two-step pathways were retained throughout much of the bacterial and archaeal domains of life and eukaryotic organelles. The indirect routes use non-discriminating aminoacyl-tRNA synthetases (non-discriminating aspartyl-tRNA synthetase and non-discriminating glutamyl-tRNA synthetase) to misaminoacylate the tRNA. The misaminoacylated tRNA formed is then transamidated into the amide aminoacyl-tRNA used in protein synthesis by tRNA-dependent amidotransferases (GatCAB and GatDE). The enzymes and tRNAs involved assemble into complexes known as transamidosomes to help maintain translational fidelity. These pathways have evolved to meet the varied cellular needs across a diverse set of organisms, leading to significant variation. In certain bacteria, the indirect pathways may provide a means to adapt to cellular stress by reducing the fidelity of protein synthesis. The retention of these indirect pathways versus acquisition of asparaginyl-tRNA synthetase and glutaminyl tRNA synthetase in lineages likely involves a complex interplay of the competing uses of glutamine and asparagine beyond translation, energetic costs, co-evolution between enzymes and tRNA, and involvement in stress response that await further investigation.

Keywords:  AspRS; GluRS; tRNA-dependent amidotransferase; tRNA-dependent biosynthesis; transamidosome

DOI:  https://doi.org/10.1002/iub.2811
Heliyon. 2024 Feb 29. 10(4): e25258

Influence of glutamine metabolism on diabetes Development:A scientometric review.

Meina Zhao, Kaiyan Wang, Rui Lin, Fei Mu, Jia Cui, Xingru Tao, Yan Weng, Jingwen Wang.

  Objective: "Metabolism affects function" is the consensus of researchers at present. It has potential clinical application value to study the effects of regulating glutamine (Gln) metabolism on diabetes physiology or pathology. Our research aimed to summarize the latest research progress, frontier hot topics and future development trends in this field from the perspective of scientometrics.Methods: Relevant literatures and reviews were obtained from the Web of Science (WoS) between January 1, 2001 and May 31, 2022. An online analysis platform of bibliometrics, CiteSpace, and VOS viewer software were used to generate visual knowledge network graphs, including publication countries, institutions and authors partnership analysis, co-occurrence analysis, co-citation analysis, as well as citations and keywords burst detection to acquire research trends and hotspots.
Results: Our results showed that a total of 945 publications in the WoS database met the analysis requirements, with articles being the main type. The overall characteristics showed an increasing trend in the number of publications and citations. The United States was leading the way in this research and was a hub for aggregating collaborations across countries. Vanderbilt University delivered high-quality impact with the most published articles. DeBerardinis, RJ in this field was the most representative author and his main research contents were Gln metabolism and mitochondrial glutaminolysis. Significantly, there was a relative lack of collaboration between institutions and authors. In addition, "type 2 diabetes", "glutamine", "metabolism", "gene expression" and "metabolomics" were the keywords categories with high frequency in co-citation references and co-occurrence cluster keywords. Analysis of popular keywords burst detection showed that "branched chain", "oxidative phosphorylation", "kinase", "insulin sensitivity", "tca cycle", "magnetic resonance spectroscopy" and "flux analysis" were new research directions and emerging methods to explore the link between Gln metabolism and diabetes. Overall, exploring Gln metabolism showed a gradual upward trend in the field of diabetes.
Conclusion: This comprehensive scientometric study identified the general outlook for the field and provided valuable guidance for ongoing research. Strategies to regulate Gln metabolism hold promise as a novel target to treat diabetes, as well as integration and intersection of multidisciplinary provides cooperation strategies and technical guarantees for the development of this field.

Keywords:  CiteSpace; Diabetes; Glutamine metabolism; Scientometric; VOSviewer

DOI:  https://doi.org/10.1016/j.heliyon.2024.e25258
Curr Issues Mol Biol. 2024 Jan 25. 46(2): 1107-1120

OCT4 Expression in Gliomas Is Dependent on Cell Metabolism.

Andrey Volnitskiy, Konstantin Shabalin, Rimma Pantina, Elena Varfolomeeva, Roman Kovalev, Vladimir Burdakov, Svetlana Emelianova, Luiza Garaeva, Alexander Yakimov, Marina Sogoyan, Michael Filatov, Andrey L Konevega, Tatiana Shtam.

  The OCT4 transcription factor is necessary to maintain cell stemness in the early stages of embryogenesis and is involved in the formation of induced pluripotent stem cells, but its role in oncogenesis is not yet entirely clear. In this work, OCT4 expression was investigated in malignant gliomas. Twenty glioma cell lines and a sample of normal adult brain tissue were used. OCT4 expression was found in all studied glioma cell lines but was not detected in normal adult brain tissue. For one of these lines, OCT4 knockdown caused tumor cell death. By varying the culture conditions of these cells, we unexpectedly found that OCT4 expression increased when cells were incubated in serum-free medium, and this effect was significantly enhanced in serum-free and L-glutamine-free medium. L-glutamine and the Krebs cycle, which is slowed down in serum-free medium according to our NMR data, are sources of α-KG. Thus, our data indicate that OCT4 expression in gliomas may be regulated by the α-KG-dependent metabolic reprogramming of cells.

Keywords:  OCT4; glioma; metabolic cell reprogramming; α-KG

DOI:  https://doi.org/10.3390/cimb46020070
Cancer Lett. 2024 Feb 17. pii: S0304-3835(24)00098-3. [Epub ahead of print] 216705

Cancer resistance and metastasis are maintained through oxidative phosphorylation.

Cemile Uslu, Eda Kapan, Alex Lyakhovich.

  Malignant tumors have increased energy requirements due to growth, differentiation or response to stress. A significant number of studies in recent years have described upregulation of mitochondrial genes responsible for oxidative phosphorylation (OXPHOS) in some tumors. Although OXPHOS is replaced by glycolysis in some tumors (Warburg effect), both processes can occur simultaneously during the evolution of the same malignancies. In particular, chemoresistant and/or cancer stem cells appear to find a way to activate OXPHOS and metastasize. In this paper, we discuss recent work showing upregulation of OXPHOS in chemoresistant tumors and cell models. In addition, we show an inverse correlation of OXPHOS gene expression with the survival time of cancer patients after chemotherapy and discuss combination therapies for resistant cancer tumors.

Keywords:  Cancer chemoprevention; Cancer chemoresistance; Cancer stem cells; Drug repurposing; Mitochondrial respiration; Oxidative phosphorylation; Personalized medicine; Targeted therapy

DOI:  https://doi.org/10.1016/j.canlet.2024.216705
Biomolecules. 2024 Feb 12. pii: 217. [Epub ahead of print]14(2):

Energy Metabolites and Indicative Significance of α-Ketoglutarate and α-Ketoglutaramate in Assessing the Progression of Chronic Hepatoencephalopathy.

Yevgeniya I Shurubor, Andrey B Krasnikov, Elena P Isakova, Yulia I Deryabina, Vladimir S Yudin, Anton A Keskinov, Boris F Krasnikov.

  In the example of a rat model with chronic hepatoencephalopathy (HE), changes in the organ morphology of rats affect the balance of metabolites of the tricarboxylic acid (TCA) cycle and metabolites of the glutamine-glutamate (Gln-Glu) cycle, namely α-ketoglutarate (αKG) and α-ketoglutaramate (αKGM), as well as the enzymes associated with them, ω-amidase (ωA) and glutamine transaminase (GTK). This model of rats was obtained as a result of 2-22 weeks of consumption by animals of hepatotoxin thioacetamide (TAA) added to drinking water at a concentration of 0.4 g/L. The control (n = 26) and TAA-induced (n = 55) groups of rats consisted of 11 cohorts each. The control cohorts consisted of 2-4 rats, and the TAA-induced cohorts consisted of 4-7 individuals. Every two weeks, samples of blood plasma, liver, kidney, and brain tissues were taken from the next cohort of rats (a total of 320 samples). By the end of the experiment, irreversible morphological changes were observed in the organs of rats: the weight of the animals was reduced up to ~45%, the weight of the kidneys up to 5%, the brain up to ~20%, and the weight of the liver increased up to ~20%. The analysis revealed: (i) a decrease in the activity of ωA and GTK in the tissues of the brain, kidneys, and liver of rats with chronic HE (by ~3, 40, and 65% and ~10, 60, and 70%, respectively); and (ii) the appearance of a significant imbalance in the content of metabolites of the Gln-Glu cycle, αKG, and αKGM. It is indicative that a ~1.5-12-fold increase in the level of αKG in the blood plasma and tissues of the organs of rats with chronic HE was accompanied by a synchronous, ~1.2-2.5-fold decrease in the level of αKGM. The data obtained indicate an essential involvement of the Gln-Glu cycle in the regulation of energy metabolism in rats under conditions of chronic HE. Attention is focused on the significance of the αKG/αKGM ratio, which can act as a potential marker for diagnosing the degree of HE development.

Keywords:  HPLC; glutamine transaminase; hepatoencephalopathy; thioacetamide; tricarboxylic acid cycle; α-ketoglutaramate; α-ketoglutarate; ω-amidase

DOI:  https://doi.org/10.3390/biom14020217
Aging Dis. 2024 Feb 01.

Glutamate Provides Cytoprotective Effect for Astrocytes Against Ischemic Insult and Promotes Astrogliosis.

Shao-Hua Yang, Yuanhong Sun, Raymond Berry, Gourav Roy Choudhury, Ali Winters, Kiran Chaudhari, Ran Liu.

Glutamate-mediated excitotoxicity has been extensively explored as a therapeutic target for the development of potential treatments of neurological disorders including stroke. However, the effect of glutamate on astrocytes under pathological conditions has been less studied. Using primary astrocyte culture, we determined the effect of glutamate on astrocytes against ischemic insult. Glutamate provided a cytoprotective effect and acted as an alternative substrate for ATP production in primary astrocytes against oxygen glucose deprivation reoxygenation insult, which was blocked by glutamate uptake inhibition. The cytoprotective effect of glutamate appears to be astrocyte-specific, as glutamate dose-dependently induces cytotoxic action in murine hippocampal HT-22 cell line. Interestingly, the cytoprotective effect of glutamate against glucose deprivation was short-last, as no protection was observed after 3-day glucose deprivation. We determined the metabolic phenotype of primary astrocyte cultured in glucose or glutamate. Primary astrocytes cultured in glutamate displayed a different metabolic phenotype when compared to those cultured in glucose, evidenced by higher basal and maximal oxygen consumption rate (OCR), higher ATP production and proton leak-coupled OCR, as well as lower glycolysis. Furthermore, glutamate exposure resulted in astrocyte activation, evidenced by an increase in astrocyte size and GFAP expression. Our study demonstrated that glutamate exerts a dual effect on astrocytes under ischemic condition. Glutamate provides an alternative substrate for energy metabolism in the absence of glucose, thereby protecting astrocytes against ischemic insults. On the other hand, glutamate exposure induces astrogliosis. Modulation of glutamate uptake and metabolism in astrocytes may provide novel targets for alleviating ischemic injury and improving function recovery after ischemic stroke.

DOI: https://doi.org/10.14336/AD.2023.0726