bims-glucam 2024-04-28 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2024‒04‒28
23 papers selected by
Sreeparna Banerjee, Middle East Technical University

Inhibition of signaling protein ERN1 increases the sensitivity of serine synthesis gene expressions to glucose and glutamine deprivations in U87MG glioblastoma cells.
Tumor‑suppressive effects of Smad‑ubiquitination regulator 2 in papillary thyroid carcinoma.
Glutamine supplementation improves the activity and immunosuppressive action of induced regulatory T cells in vitro and in vivo.
Wild-type IDH2 is a therapeutic target for triple-negative breast cancer.
CircCOL1A1 promotes proliferation, migration, and invasion of colorectal cancer (CRC) cells and glutamine metabolism through GLS1 up-regulation by sponging miR-214-3p.
Metabolomics captures the differential metabolites in the replication pathway of snakehead vesiculovirus regulated by glutamine.
Mitochondrial-Stem Cell Connection: Providing Additional Explanations for Understanding Cancer.
The Tumor Microenvironment: Signal Transduction.
Metabolic Profiling of SH-SY5Y and Neuro2A Cells in Relation to Fetal Calf Serum (FCS) Concentration in Culture Media.
The γ-glutamyl cycle serves as an amino acids supply system in colorectal cancer organoids under chronic hypoxia.
Porphyrin overdrive rewires cancer cell metabolism.
Cancer cell metabolism and antitumour immunity.
Gefitinib Induces Apoptosis in NSCLC Cells by Promoting Glutaminolysis and Inhibiting the MEK/ERK Signaling Pathway.
Warburg Effect Reshapes Tumor Immunogenicity.
Metabolic vulnerability of cancer stem cells and their niche.
Metabolomics-driven discovery of therapeutic targets for cancer cachexia.
[Research Progress of Isocitrate Dehydrogenase Mutation-Positive Acute Myeloid Leukemia --Review].
Discovery of Novel Dual Inhibitors Targeting Mutant IDH1 and NAMPT for the Treatment of Glioma with IDH1Mutation.
Construction of glutathione-responsive paclitaxel prodrug nanoparticles for image-guided targeted delivery and breast cancer therapy.
Regulation of Molecular Biomarkers Associated with the Progression of Prostate Cancer.
Bidirectional dysregulation of synaptic glutamate signaling after transient metabolic failure.
Colonic Dysregulation of Major Metabolic Pathways in Experimental Ulcerative Colitis.
Glutathione Induces Keap1 S-Glutathionylation and Mitigates Oscillating Glucose-Induced β-Cell Dysfunction by Activating Nrf2.

Endocr Regul. 2024 Jan 01. 58(1): 91-100

Inhibition of signaling protein ERN1 increases the sensitivity of serine synthesis gene expressions to glucose and glutamine deprivations in U87MG glioblastoma cells.

Oleksandr H Minchenko, Myroslava Y Sliusar, Olena O Khita, Dmytro O Minchenko, Yuliia M Viletska, Oleh V Halkin, Liudmyla O Levadna, Anastasiia A Cherednychenko, Yevgen P Khikhlo.

  Objective. Glucose and glutamine supply as well as serine synthesis and endoplasmic reticulum (ER) stress are important factors of glioblastoma growth. Previous studies showed that the knockdown of ERN1 (ER to nucleus signaling 1) suppressed glioblastoma cell proliferation and modified the sensitivity of numerous gene expressions to nutrient deprivations. The present study is aimed to investigate the impact of glucose and glutamine deprivations on the expression of serine synthesis genes in U87MG glioblastoma cells in relation to ERN1 knockdown with the intent to reveal the role of ERN1 signaling pathway on the ER stress-dependent regulation of these gene expressions. Clarification of the regulatory mechanisms of serine synthesis is a great significance for glioblastoma therapy. Methods. The control U87MG glioblastoma cells (transfected by empty vector) and ERN1 knockdown cells (transfected by dominant-negative ERN1) were exposed under glucose and glutamine deprivation conditions for 16 h. RNA was extracted from cells and reverse transcribed. The expression level of PHGDH (phosphoglycerate dehydrogenase), PSAT1 (phosphoserine amino-transferase 1), PSPH (phosphoserine phosphatase), ATF4 (activating transcription factor 4), and SHMT1 (serine hydroxymethyltransferase 1) genes was studied by real-time qPCR and normalized to ACTB. Results. It was found that the expression level of genes responsible for serine synthesis such as PHGDH, PSAT1, PSPH, and transcription factor ATF4 was up-regulated in U87MG glioblastoma cells under glucose and glutamine deprivations. Furthermore, inhibition of ERN1 significantly enhances the impact of glucose and especially glutamine deprivations on these gene expressions. At the same time, the expression of the SHMT1 gene, which is responsible for serine conversion to glycine, was down-regulated in both nutrient deprivation conditions with more significant changes in ERN1 knockdown glioblastoma cells. Conclusion. Taken together, the results of present study indicate that the expression of genes responsible for serine synthesis is sensitive to glucose and glutamine deprivations in gene-specific manner and that suppression of ERN1 signaling significantly modifies the impact of both glucose and glutamine deprivations on PHGDH, PSAT1, PSPH, ATF4, and SHMT1 gene expressions and reflects the ERN1-mediated genome reprograming introduced by nutrient deprivation condition.

Keywords:  ATF4; ERN1 knockdown; PSAT1; PSPH; U87MG glioblastoma cells; gene expression; glucose deprivation; glutamine deprivation

DOI:  https://doi.org/10.2478/enr-2024-0010
Oncol Lett. 2024 Jun;27(6): 263

Tumor‑suppressive effects of Smad‑ubiquitination regulator 2 in papillary thyroid carcinoma.

Guirong Luo, Liting Zhang, Lihong Zhang, Wenyi Wu, Jianqing Lin, Haihong Shi, Yihuang Yu, Weigang Qiu, Jinyan Chen, Hansen Ding, Xinyao Chen.

  Smad-ubiquitination regulator 2 (SMURF2) functions as a homolog of E6AP carboxyl terminus-type E3 ubiquitin ligase to regulate cell cycle progression and tumor growth factor expression. SMURF2 has been revealed to function as a tumor suppressor in a number of cancers; however, its function in papillary thyroid carcinoma (PTC) remains largely unknown. Therefore, the aim of the present study was to investigate the function of SMURF2 in PTC. Reverse transcription-quantitative PCR and western blotting were used to detect cellular expression of SMURF2 in vitro. After increasing or inhibiting the expression of SMURF2, MTT was used to detect the effect on tumor cell proliferation and Transwell assays were used to detect the effect on tumor cell migration and invasion. Finally, ELISA was used to detect the effects on glucose and glutamine metabolism in tumor cells and the findings revealed that SMURF2 was downregulated in PTC tissues. Moreover, SMURF2 inhibited the proliferation, invasion and migration of PTC cells, and promoted their apoptosis. Finally, SMURF2 inhibited cell glycolysis and glutaminolysis and affected metabolism in the PTC cell line, TPC-1. Thus, the findings of the present study suggest that SMURF2 may be a potential target in the treatment of PTC.

Keywords:  Smad-ubiquitination regulator 2; Warburg effect; glutamine metabolism; papillary thyroid carcinoma

DOI:  https://doi.org/10.3892/ol.2024.14396
Transpl Immunol. 2024 Apr 23. pii: S0966-3274(24)00060-1. [Epub ahead of print] 102044

Glutamine supplementation improves the activity and immunosuppressive action of induced regulatory T cells in vitro and in vivo.

Li Zhang, Zhongya Xu, Yuanjiu Li, Ke-Jia Wu, Chongyuan Yu, Wenjie Zhu, Dong-Lin Sun, Li Zhu, Jun Zhou.

  BACKGROUND: Glutamine is crucial for the activation and efficacy of T cells, and may play a role in regulating the immune environment. This study aimed to investigate the potential role of glutamine in the activation and proliferation of induced regulatory T cells (iTregs).METHODS: CD4+CD45RA+T cells were sorted from peripheral blood mononuclear cells and cultured to analyze iTreg differentiation. Glutamine was then added to the culture system to evaluate the effects of glutamine on iTregs by determining oxidative phosphorylation (OXPHOS), apoptosis, and cytokine secretion. Additionally, a humanized murine graft-versus-host disease (GVHD) model was constructed to confirm the efficacy of glutamine-treated iTregs in vivo.
RESULTS: After being cultured in vitro, glutamine significantly enhanced the levels of Foxp3, CTLA-4, CD39, CD69, IL-10, TGF-β, and Ki67 (CTLA-4, IL-10, TGF-β are immunosuppressive markers of iTregs) compared with that of the control iTregs (P < 0.05). Furthermore, the growth curve showed that the proliferative ability of glutamine-treated iTregs was better than that of the control iTregs (P < 0.01). Compared with the control iTregs, glutamine supplementation significantly increased oxygen consumption rates and ATP production (P < 0.05), significantly downregulated Annexin V and Caspase 3, and upregulated BCL2 (P < 0.05). However, GPNA significantly reversed the effects of glutamine (P < 0.05). Finally, a xeno-GVHD mouse model was successfully established to confirm that glutamine-treated iTregs increased the mice survival rate, delayed weight loss, and alleviated colon injury.
CONCLUSION: Glutamine supplementation can improve the activity and immunosuppressive action of iTregs, and the possible mechanisms by which this occurs are related to cell proliferation, apoptosis, and OXPHOS.

Keywords:  Apoptosis; Glutamine; Immunosuppressive action; Oxidative phosphorylation; iTreg

DOI:  https://doi.org/10.1016/j.trim.2024.102044
Nat Commun. 2024 Apr 24. 15(1): 3445

Wild-type IDH2 is a therapeutic target for triple-negative breast cancer.

Jiang-Jiang Li, Tiantian Yu, Peiting Zeng, Jingyu Tian, Panpan Liu, Shuang Qiao, Shijun Wen, Yumin Hu, Qiao Liu, Wenhua Lu, Hui Zhang, Peng Huang.

Mutations in isocitrate dehydrogenases (IDH) are oncogenic events due to the generation of oncogenic metabolite 2-hydroxyglutarate. However, the role of wild-type IDH in cancer development remains elusive. Here we show that wild-type IDH2 is highly expressed in triple negative breast cancer (TNBC) cells and promotes their proliferation in vitro and tumor growth in vivo. Genetic silencing or pharmacological inhibition of wt-IDH2 causes a significant increase in α-ketoglutarate (α-KG), indicating a suppression of reductive tricarboxylic acid (TCA) cycle. The aberrant accumulation of α-KG due to IDH2 abrogation inhibits mitochondrial ATP synthesis and promotes HIF-1α degradation, leading to suppression of glycolysis. Such metabolic double-hit results in ATP depletion and suppression of tumor growth, and renders TNBC cells more sensitive to doxorubicin treatment. Our study reveals a metabolic property of TNBC cells with active utilization of glutamine via reductive TCA metabolism, and suggests that wild-type IDH2 plays an important role in this metabolic process and could be a potential therapeutic target for TNBC.

DOI: https://doi.org/10.1038/s41467-024-47536-6
J Cancer Res Clin Oncol. 2024 Apr 25. 150(4): 211

CircCOL1A1 promotes proliferation, migration, and invasion of colorectal cancer (CRC) cells and glutamine metabolism through GLS1 up-regulation by sponging miR-214-3p.

Jia Liu, Xianbo Zhang, Meijian Yang, Xianghong Zhang.

  BACKGROUND: Circular ribose nucleic acids (circRNAs), an abundant type of noncoding RNAs, are widely expressed in eukaryotic cells and exert a significant impact on the initiation and progression of various disorders, including different types of cancer. However, the specific role of various circRNAs in colorectal cancer (CRC) pathology is still not fully understood.METHODS: The initial step involved the use of quantitative reverse transcription polymerase chain reaction (RT-qPCR) to assess the expression levels of circRNAs and messenger RNA (mRNA) in CRC cell lines and tissues. Subsequently, functional analyses of circCOL1A1 knockdown were conducted in vitro and in vivo through cell counting kit (CCK)-8, colony formation and transwell assays, as well as xenograft mouse model of tumor formation. Molecular expression and interactions were investigated using luciferase reporter assays, Western blot analysis, RNA immunoprecipitation (RIP), and immunohistochemical staining.
RESULTS: The RT-qPCR results revealed elevated levels of circCOL1A1 expressions in CRC tissues and cell lines as compared to the normal counterparts. In addition, circCOL1A1 expression level was found to be correlated with TNM stage, lymph node metastases, distant metastases, and invasion. Knockdown of circCOL1A1 resulted in impaired invasion, migration, and proliferation of CRC cells, and suppressed tumor generation in the animal model. We further demonstrated that circCOL1A1 could act as a sponge for miR-214-3p, suppressing miR-214-3p activity and leading to the upregulation of GLS1 protein to promote glutamine metabolism.
CONCLUSION: These findings suggest that circCOL1A1 functions as an oncogenic molecule to promote CRC progression via miR-214-3p/GLS1 axis, hinting on the potential of circCOL1A1 as a therapeutic target for CRC.

Keywords:  Colorectal cancer; circCOL1A1; miR-214-3p/GLS1 axis

DOI:  https://doi.org/10.1007/s00432-024-05736-z
Dis Aquat Organ. 2024 Apr 25. 158 101-114

Metabolomics captures the differential metabolites in the replication pathway of snakehead vesiculovirus regulated by glutamine.

Binbin Sun, Yulei Zhang, Keping Chen, Lindan Sun.

  Snakehead vesiculovirus (SHVV) is a negative-sense single-stranded RNA virus that infects snakehead fish. This virus leads to illness and mortality, causing significant economic losses in the snakehead aquaculture industry. The replication and spread of SHVV in cells, which requires glutamine as a nitrogen source, is accompanied by alterations in intracellular metabolites. However, the metabolic mechanisms underlying the inhibition of viral replication by glutamine deficiency are poorly understood. This study utilized liquid chromatography-mass spectrometry to measure the differential metabolites between the channel catfish Parasilurus asotus ovary cell line infected with SHVV under glutamine-containing and glutamine-deprived conditions. Results showed that the absence of glutamine regulated 4 distinct metabolic pathways and influenced 9 differential metabolites. The differential metabolites PS(16:0/16:0), 5,10-methylene-THF, and PS(18:0/18:1(9Z)) were involved in amino acid metabolism. In the nuclear metabolism functional pathway, differential metabolites of guanosine were observed. In the carbohydrate metabolism pathway, differential metabolites of UDP-d-galacturonate were detected. In the signal transduction pathway, differential metabolites of SM(d18:1/20:0), SM(d18:1/22:1(13Z)), SM(d18:1/24:1(15 Z)), and sphinganine were found. Among them, PS(18:0/18:1(9Z)), PS(16:0/16:0), and UDP-d-galacturonate were involved in the synthesis of phosphatidylserine and glycoprotein. The compound 5,10-methylene-THF provided raw materials for virus replication, and guanosine and sphingosine are related to virus virulence. The differential metabolites may collectively participate in the replication, packaging, and proliferation of SHVV under glutamine deficiency. This study provides new insights and potential metabolic targets for combating SHVV infection in aquaculture through metabolomics approaches.

Keywords:  Glutamine-deprived; Metabolomics; Snakehead fish; Snakehead vesiculovirus; Ultra-high-performance liquid chromatography

DOI:  https://doi.org/10.3354/dao03786
Metabolites. 2024 Apr 17. pii: 229. [Epub ahead of print]14(4):

Mitochondrial-Stem Cell Connection: Providing Additional Explanations for Understanding Cancer.

Pierrick Martinez, Ilyes Baghli, Géraud Gourjon, Thomas N Seyfried.

  The cancer paradigm is generally based on the somatic mutation model, asserting that cancer is a disease of genetic origin. The mitochondrial-stem cell connection (MSCC) proposes that tumorigenesis may result from an alteration of the mitochondria, specifically a chronic oxidative phosphorylation (OxPhos) insufficiency in stem cells, which forms cancer stem cells (CSCs) and leads to malignancy. Reviewed evidence suggests that the MSCC could provide a comprehensive understanding of all the different stages of cancer. The metabolism of cancer cells is altered (OxPhos insufficiency) and must be compensated by using the glycolysis and the glutaminolysis pathways, which are essential to their growth. The altered mitochondria regulate the tumor microenvironment, which is also necessary for cancer evolution. Therefore, the MSCC could help improve our understanding of tumorigenesis, metastases, the efficiency of standard treatments, and relapses.

Keywords:  cancer stem cells; glutaminolysis; glycolysis; metastases; oxidative phosphorylation; tumor microenvironment; tumorigenesis

DOI:  https://doi.org/10.3390/metabo14040229
Biomolecules. 2024 Apr 04. pii: 438. [Epub ahead of print]14(4):

The Tumor Microenvironment: Signal Transduction.

Xianhong Zhang, Haijun Ma, Yue Gao, Yabing Liang, Yitian Du, Shuailin Hao, Ting Ni.

  In the challenging tumor microenvironment (TME), tumors coexist with diverse stromal cell types. During tumor progression and metastasis, a reciprocal interaction occurs between cancer cells and their environment. These interactions involve ongoing and evolving paracrine and proximal signaling. Intrinsic signal transduction in tumors drives processes such as malignant transformation, epithelial-mesenchymal transition, immune evasion, and tumor cell metastasis. In addition, cancer cells embedded in the tumor microenvironment undergo metabolic reprogramming. Their metabolites, serving as signaling molecules, engage in metabolic communication with diverse matrix components. These metabolites act as direct regulators of carcinogenic pathways, thereby activating signaling cascades that contribute to cancer progression. Hence, gaining insights into the intrinsic signal transduction of tumors and the signaling communication between tumor cells and various matrix components within the tumor microenvironment may reveal novel therapeutic targets. In this review, we initially examine the development of the tumor microenvironment. Subsequently, we delineate the oncogenic signaling pathways within tumor cells and elucidate the reciprocal communication between these pathways and the tumor microenvironment. Finally, we give an overview of the effect of signal transduction within the tumor microenvironment on tumor metabolism and tumor immunity.

Keywords:  signaling pathways; tumor immunity; tumor metabolism; tumor microenvironment

DOI:  https://doi.org/10.3390/biom14040438
Metabolites. 2024 Mar 26. pii: 188. [Epub ahead of print]14(4):

Metabolic Profiling of SH-SY5Y and Neuro2A Cells in Relation to Fetal Calf Serum (FCS) Concentration in Culture Media.

Lys Kronenberger, Janine Mett, Jessica Hoppstädter, Uli Müller.

  The neuroblastoma cell lines SH-SY5Y and Neuro2A are commonly utilized models in neurobiological research. DMEM supplemented with different nutrients and 5-10% Fetal Calf Serum (FCS) is typically used for culturing these cell lines. During special treatments, a reduced FCS content is often deployed to reduce cellular proliferation or the content of bioactive compounds. The impact of the reduction of FCS in culture media on the metabolic profile of SH-SY5Y and Neuro2A cells is currently unknown. Using an Amplex Red Assay, this study showed that the consumption of L-glutamine decreased after FCS reduction. Glucose and pyruvate consumption increased in both cell lines after the reduction of FCS. Thus, lactate production also increased with reduced FCS concentration. The reduction of FCS in the cell culture medium resulted in a reduced aerobic ATP production for SH-SY5Y cells and a complete shut down of aerobic ATP production for Neuro2A cells, measured using the Seahorse XF Real-Time ATP Rate Assay. Utilizing the Seahorse XF Glutamine Oxidation Stress Test, Neuro2A cells showed an increased utilization of L-glutamine oxidation after reduction of FCS. These results indicate that changes in FCS concentration in culture media have an impact on the different energy production strategies of SH-SY5Y and Neuro2A cells which must be considered when planning special treatments.

Keywords:  Neuro2A; SH-SY5Y; glucose; glutamine; lactate; metabolism; physiological cell culture; pyruvate

DOI:  https://doi.org/10.3390/metabo14040188
Biochem Biophys Res Commun. 2024 Apr 22. pii: S0006-291X(24)00513-8. [Epub ahead of print]714 149977

The γ-glutamyl cycle serves as an amino acids supply system in colorectal cancer organoids under chronic hypoxia.

Sho Tabata, Hiroko Endo, Hideki Makinoshima, Tomoyoshi Soga, Masahiro Inoue.

  Malignant tumors are characterized by a hypoxic microenvironment, and metabolic reprogramming is necessary to ensure energy production and oxidative stress resistance. Although the microenvironmental properties of tumors vary under acute and chronic hypoxia, studies on chronic hypoxia-induced metabolic changes are limited. In the present study, we performed a comprehensive metabolic analysis in a chronic hypoxia model using colorectal cancer (CRC) organoids, and identified an amino acid supply system through the γ-glutamyl cycle, a glutathione recycling pathway. We analyzed the metabolic changes caused by hypoxia over time and observed that chronic hypoxia resulted in an increase in 5-oxoproline and a decrease in oxidized glutathione (GSSG) compared to acute hypoxia. These findings suggest that chronic hypoxia induces metabolic changes in the γ-glutamyl cycle. Moreover, inhibition of the γ-glutamyl cycle via γ-glutamyl cyclotransferase (GGCT) and γ-glutamyl transferase 1 (GGT1) knockdown significantly reversed chronic hypoxia-induced upregulation of 5-oxoproline and several amino acids. Notably, GGT1 knockdown downregulated the intracellular levels of γ-glutamyl amino acids. Conclusively, these results indicate that the γ-glutamyl cycle serves as an amino acid supply system in CRC under chronic hypoxia, which provides fresh insight into cancer metabolism under chronic hypoxia.

Keywords:  Amino acid metabolism; CTOS; Colorectal cancer; Organoid; γ-glutamyl amino acids; γ-glutamyl cycle

DOI:  https://doi.org/10.1016/j.bbrc.2024.149977
Life Sci Alliance. 2024 Jul;pii: e202302547. [Epub ahead of print]7(7):

Porphyrin overdrive rewires cancer cell metabolism.

Swamy R Adapa, Gregory A Hunter, Narmin E Amin, Christopher Marinescu, Andrew Borsky, Elizabeth M Sagatys, Said M Sebti, Gary W Reuther, Gloria C Ferreira, Rays Hy Jiang.

All cancer cells reprogram metabolism to support aberrant growth. Here, we report that cancer cells employ and depend on imbalanced and dynamic heme metabolic pathways, to accumulate heme intermediates, that is, porphyrins. We coined this essential metabolic rewiring "porphyrin overdrive" and determined that it is cancer-essential and cancer-specific. Among the major drivers are genes encoding mid-step enzymes governing the production of heme intermediates. CRISPR/Cas9 editing to engineer leukemia cell lines with impaired heme biosynthetic steps confirmed our whole-genome data analyses that porphyrin overdrive is linked to oncogenic states and cellular differentiation. Although porphyrin overdrive is absent in differentiated cells or somatic stem cells, it is present in patient-derived tumor progenitor cells, demonstrated by single-cell RNAseq, and in early embryogenesis. In conclusion, we identified a dependence of cancer cells on non-homeostatic heme metabolism, and we targeted this cancer metabolic vulnerability with a novel "bait-and-kill" strategy to eradicate malignant cells.

DOI: https://doi.org/10.26508/lsa.202302547
Nat Rev Immunol. 2024 Apr 22.

Cancer cell metabolism and antitumour immunity.

Mara De Martino, Jeffrey C Rathmell, Lorenzo Galluzzi, Claire Vanpouille-Box.

Accumulating evidence suggests that metabolic rewiring in malignant cells supports tumour progression not only by providing cancer cells with increased proliferative potential and an improved ability to adapt to adverse microenvironmental conditions but also by favouring the evasion of natural and therapy-driven antitumour immune responses. Here, we review cancer cell-intrinsic and cancer cell-extrinsic mechanisms through which alterations of metabolism in malignant cells interfere with innate and adaptive immune functions in support of accelerated disease progression. Further, we discuss the potential of targeting such alterations to enhance anticancer immunity for therapeutic purposes.

DOI: https://doi.org/10.1038/s41577-024-01026-4
Discov Med. 2024 Apr;36(183): 836-841

Gefitinib Induces Apoptosis in NSCLC Cells by Promoting Glutaminolysis and Inhibiting the MEK/ERK Signaling Pathway.

Yakun Zhang, Haixin Liu, Xianyan Liu, Lianqun Lang.

  BACKGROUND: Over 80% of lung cancer cases constitute non-small cell lung cancer (NSCLC), making it the most prevalent type of lung cancer globally and the leading cause of cancer-related deaths. The treatment of NSCLC patients with gefitinib has demonstrated promising initial efficacy. However, the underlying mechanism remains unclear. This study aims to investigate how gefitinib affects the mitogen-activated protein kinase kinase (MEK)/extracellular regulated protein kinases (ERK) signaling pathway-mediated growth and death of NSCLC cells.METHODS: In this study, the NSCLC cell line A549 was cultured in vitro and divided into a control group and a gefitinib group. The viability of the A549 cells was assessed using the methylthiazolyldiphenyl-tetrazolium bromide (MTT) assay. Flow cytometry was employed to detect apoptosis in A549 cells, and the expression of glutamate dehydrogenase (GDH1) mRNA in these cells was determined using real-time quantitative PCR (RT-PCR). Western blotting was utilized to evaluate the protein expression levels of key components in the MEK/ERK signaling pathway, including phospho-MEK1/2, MEK1/2, phospho-ERK1/2, and ERK1/2. Additionally, intracellular glutamine content in A549 cells was measured using a colorimetric method.
RESULTS: In contrast to the control group, the proliferation of A549 cells, the transcription level of glutamate dehydrogenase (GDH1), the intracellular glutamine content, and the protein expression levels of phospho-MEK1/2 and phospho-ERK1/2 were significantly lower in the gefitinib group. Moreover, apoptosis markedly increased.
CONCLUSIONS: Gefitinib expedites apoptosis and diminishes proliferation in the NSCLC cell line A549 by downregulating the epidermal growth factor receptor (EGFR)/MEK/ERK signaling pathway. This effect is accomplished by fostering the expression of GDH1 to augment glutaminolysis in A549 cells.

Keywords:  MEK/ERK pathway; NSCLC; apoptosis; gefitinib; glutaminolysis

DOI:  https://doi.org/10.24976/Discov.Med.202436183.78
Cancer Res. 2024 Apr 24.

Warburg Effect Reshapes Tumor Immunogenicity.

Jose A Enríquez, María Mittelbrunn.

Tumor cells rewire their metabolism to fulfill the demands of highly proliferative cells. This changes cellular metabolism to adapt to fuel and oxygen availability for energy production and to increase the synthesis capacity of building blocks for cell division and growth. In addition, the metabolic shift also modulates the immunogenicity of the tumor cells. Recently, Mahmood and colleagues reported a connection between mitochondrial DNA mutations in cancer cells and their response to immunotherapy in a mouse model of melanoma.

DOI: https://doi.org/10.1158/0008-5472.CAN-24-1304
Front Pharmacol. 2024 ;15 1375993

Metabolic vulnerability of cancer stem cells and their niche.

Laura Marrone, Simona Romano, Chiara Malasomma, Valeria Di Giacomo, Andrea Cerullo, Rosetta Abate, Marialuisa Alessandra Vecchione, Deborah Fratantonio, Maria Fiammetta Romano.

  Cancer stem cells (CSC) are the leading cause of the failure of anti-tumor treatments. These aggressive cancer cells are preserved and sustained by adjacent cells forming a specialized microenvironment, termed niche, among which tumor-associated macrophages (TAMs) are critical players. The cycle of tricarboxylic acids, fatty acid oxidation path, and electron transport chain have been proven to play central roles in the development and maintenance of CSCs and TAMs. By improving their oxidative metabolism, cancer cells are able to extract more energy from nutrients, which allows them to survive in nutritionally defective environments. Because mitochondria are crucial bioenergetic hubs and sites of these metabolic pathways, major hopes are posed for drugs targeting mitochondria. A wide range of medications targeting mitochondria, electron transport chain complexes, or oxidative enzymes are currently investigated in phase 1 and phase 2 clinical trials against hard-to-treat tumors. This review article aims to highlight recent literature on the metabolic adaptations of CSCs and their supporting macrophages. A focus is provided on the resistance and dormancy behaviors that give CSCs a selection advantage and quiescence capacity in particularly hostile microenvironments and the role of TAMs in supporting these attitudes. The article also describes medicaments that have demonstrated a robust ability to disrupt core oxidative metabolism in preclinical cancer studies and are currently being tested in clinical trials.

Keywords:  anti-mitochondrial drugs in clinical trials; cancer stem cells; oxidative metabolism; tumor associated macrophages; tumor dormancy

DOI:  https://doi.org/10.3389/fphar.2024.1375993
J Cachexia Sarcopenia Muscle. 2024 Apr 21.

Metabolomics-driven discovery of therapeutic targets for cancer cachexia.

Pengfei Cui, Xiaoyi Li, Caihua Huang, Donghai Lin.

  Cancer cachexia (CC) is a devastating metabolic syndrome characterized by skeletal muscle wasting and body weight loss, posing a significant burden on the health and survival of cancer patients. Despite ongoing efforts, effective treatments for CC are still lacking. Metabolomics, an advanced omics technique, offers a comprehensive analysis of small-molecule metabolites involved in cellular metabolism. In CC research, metabolomics has emerged as a valuable tool for identifying diagnostic biomarkers, unravelling molecular mechanisms and discovering potential therapeutic targets. A comprehensive search strategy was implemented to retrieve relevant articles from primary databases, including Web of Science, Google Scholar, Scopus and PubMed, for CC and metabolomics. Recent advancements in metabolomics have deepened our understanding of CC by uncovering key metabolic signatures and elucidating underlying mechanisms. By targeting crucial metabolic pathways including glucose metabolism, amino acid metabolism, fatty acid metabolism, bile acid metabolism, ketone body metabolism, steroid metabolism and mitochondrial energy metabolism, it becomes possible to restore metabolic balance and alleviate CC symptoms. This review provides a comprehensive summary of metabolomics studies in CC, focusing on the discovery of potential therapeutic targets and the evaluation of modulating specific metabolic pathways for CC treatment. By harnessing the insights derived from metabolomics, novel interventions for CC can be developed, leading to improved patient outcomes and enhanced quality of life.

Keywords:  Cancer cachexia; Metabolic pathway; Metabolomics; Therapeutic target

DOI:  https://doi.org/10.1002/jcsm.13465
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2024 Apr;32(2): 630-633

[Research Progress of Isocitrate Dehydrogenase Mutation-Positive Acute Myeloid Leukemia --Review].

Fang Ye, Jie Ma.

  Isocitrate dehydrogenase (IDH) is an enzymes involved in a variety of metabolic and epigenetic processes. IDH can be detected in approximately 20% of patients with acute myeloid leukemia (AML), the mutated IDH enzyme acquires new oncogenic enzyme activity and converts α-ketoglutaric acid (α-KG) to the tumor metabolite 2-hydroxyglutaric acid (2-HG), which accumulates at high levels in cells and hinders the function of αKG-dependent enzymes, including epigenetic regulators, resulting in DNA hypermethylation, abnormal gene expression, cell proliferation, and abnormal differentiation, and contributes to leukemia disease progression. IDH mutations have different effects on the prognosis of patients with AML depending on the location of the mutation and other co-occurring genomic abnormalities. This paper will review the latest research progress on the IDH positive AML gene changes, prognosis, and inhibitors.

Keywords:  IDH mutation； acute myelocytic leukemia； IDH inhibitor

DOI:  https://doi.org/10.19746/j.cnki.issn.1009-2137.2024.02.046
J Med Chem. 2024 Apr 23.

Discovery of Novel Dual Inhibitors Targeting Mutant IDH1 and NAMPT for the Treatment of Glioma with IDH1Mutation.

Fei Wen, Gang Gui, Xiaoyu Wang, Anqi Qin, Tianfang Ma, Hui Chen, Chunzheng Li, Xiaoming Zha.

The targeting of cancer cell intrinsic metabolism has emerged as a promising strategy for antitumor intervention. In the study, we identified the first-in-class small molecules that effectively inhibit both mutant isocitrate dehydrogenase 1 (mIDH1) and nicotinamide phosphoribosyltransferase (NAMPT), two crucial targets in cancer metabolism, through structure-based drug design. Notably, compound 23h exhibits excellent and balanced inhibitory activities against both mIDH1 (IC50 = 14.93 nM) and NAMPT (IC50 = 12.56 nM), leading to significant suppression of IDH1-mutated glioma cell (U87 MG-IDH1R132H) proliferation. Significantly, compound 23h has the ability to cross the blood-brain barrier (B/P ratio, 0.76) and demonstrates remarkable in vivo antitumor efficacy (20 mg/kg) in the U87 MG-IDH1R132H orthotopic transplantation mouse models without any notable toxicity. This proof-of-concept investigation substantiates the viability of discovering small molecules that concurrently target mIDH1 and NAMPT, providing valuable leads for the treatment of glioma and an efficient approach for the discovery of multitarget antitumor drugs.

DOI: https://doi.org/10.1021/acs.jmedchem.3c02482
RSC Adv. 2024 Apr 16. 14(18): 12796-12806

Construction of glutathione-responsive paclitaxel prodrug nanoparticles for image-guided targeted delivery and breast cancer therapy.

Weiwei Ma, Qiufeng Zhao, Shilong Zhu, Xinyue Wang, Chuangchuang Zhang, Daming Ma, Na Li, Yanyan Yin.

Paclitaxel (PTX) remains an essential drug in the treatment of breast cancer. To improve metabolic stability and real-time monitoring of drug location, we develop a visualized nano-prodrug. Novel hyaluronic acid (HA)-coated glutathione (GSH)-sensitive chitosan (CS)-based nano-prodrug (HA/TPE-CS-SS-PTX NPs) with aggregation-induced emission effects (AIE) were accomplished. The prodrug NPs (drug loading 29.32%, particle size 105 nm, regular sphericity) exhibit excellent fluorescence stability. The prodrug NPs could target tumor cells with high expression of CD44 and decompose in the presence of high concentrations of glutathione. In vitro evaluations revealed that the prodrug NPs have significant cytotoxicity on 4T1 cells, and due to their excellent AIE characteristics, their position in cells can be tracked. Moreover, the prodrug NPs also shown superior anti-tumor effects in vivo experimental. Overall, the HA/TPE-CS-SS-PTX NPs we constructed have excellent bio-imaging capabilities and can be served as a potential nanomedicine for PTX delivery against breast cancer.

DOI: https://doi.org/10.1039/d4ra00610k
Int J Mol Sci. 2024 Apr 10. pii: 4171. [Epub ahead of print]25(8):

Regulation of Molecular Biomarkers Associated with the Progression of Prostate Cancer.

Miguel Martin-Caraballo.

  Androgen receptor signaling regulates the normal and pathological growth of the prostate. In particular, the growth and survival of prostate cancer cells is initially dependent on androgen receptor signaling. Exposure to androgen deprivation therapy leads to the development of castration-resistant prostate cancer. There is a multitude of molecular and cellular changes that occur in prostate tumor cells, including the expression of neuroendocrine features and various biomarkers, which promotes the switch of cancer cells to androgen-independent growth. These biomarkers include transcription factors (TP53, REST, BRN2, INSM1, c-Myc), signaling molecules (PTEN, Aurora kinases, retinoblastoma tumor suppressor, calcium-binding proteins), and receptors (glucocorticoid, androgen receptor-variant 7), among others. It is believed that genetic modifications, therapeutic treatments, and changes in the tumor microenvironment are contributing factors to the progression of prostate cancers with significant heterogeneity in their phenotypic characteristics. However, it is not well understood how these phenotypic characteristics and molecular modifications arise under specific treatment conditions. In this work, we summarize some of the most important molecular changes associated with the progression of prostate cancers and we describe some of the factors involved in these cellular processes.

Keywords:  biomarkers; castration-resistant prostate cancer; interleukin-6; neuroendocrine differentiation; prostate cancer; signaling

DOI:  https://doi.org/10.3390/ijms25084171
bioRxiv. 2024 Apr 12. pii: 2024.04.11.588988. [Epub ahead of print]

Bidirectional dysregulation of synaptic glutamate signaling after transient metabolic failure.

Stefan Passlick, Ghanim Ullah, Christian Henneberger.

Ischemia leads to a severe dysregulation of glutamate homeostasis and excitotoxic cell damage in the brain. Shorter episodes of energy depletion, for instance during peri-infarct depolarizations, can also acutely perturb glutamate signaling. It is less clear if such episodes of metabolic failure also have persistent effects on glutamate signaling and how the relevant mechanisms such as glutamate release and uptake are differentially affected. We modelled acute and transient metabolic failure by using a chemical ischemia protocol and analyzed its effect on glutamatergic synaptic transmission and extracellular glutamate signals by electrophysiology and multiphoton imaging, respectively, in the hippocampus. Our experiments uncover a duration-dependent bidirectional dysregulation of glutamate signaling. Whereas short chemical ischemia induces a lasting potentiation of presynaptic glutamate release and synaptic transmission, longer episodes result in a persistent postsynaptic failure of synaptic transmission. We also observed an unexpected hierarchy of vulnerability of the involved mechanisms and cell types. Axonal action potential firing and glutamate uptake were unexpectedly resilient compared to postsynaptic cells, which overall were most vulnerable to acute and transient metabolic stress. We conclude that even short perturbations of energy supply lead to a lasting potentiation of synaptic glutamate release, which may increase glutamate excitotoxicity well beyond the metabolic incident.

DOI: https://doi.org/10.1101/2024.04.11.588988
Metabolites. 2024 Mar 29. pii: 194. [Epub ahead of print]14(4):

Colonic Dysregulation of Major Metabolic Pathways in Experimental Ulcerative Colitis.

Ji Yeon Noh, Naser Farhataziz, Michael T Kinter, Xin Yan, Yuxiang Sun.

  Inflammatory bowel disease (IBD) is multifactorial chronic inflammatory disease in the gastrointestinal tract, affecting patients' quality of life profoundly. The incidence of IBD has been on the rise globally for the last two decades. Because the molecular mechanisms underlying the disease remain not well understood, therapeutic development is significantly impeded. Metabolism is a crucial cellular process to generate the energy needed for an inflammatory response and tissue repair. Comprehensive understanding of the metabolic pathways in IBD would help to unravel the disease pathogenesis/progression and facilitate therapeutic discoveries. Here, we investigated four metabolic pathways altered in experimental colitis. C57BL/6J mice were treated with dextran sulfate sodium (DSS) in drinking water for 7 days to induce experimental ulcerative colitis (UC). We conducted proteomics analysis for the colon samples using LC/MS, to profile key metabolic intermediates. Our findings revealed significant alterations in four major metabolic pathways: antioxidative defense, β-oxidation, glycolysis, and TCA cycle pathways. The energy metabolism by β-oxidation, glycolysis, and TCA cycle pathways were downregulated under UC, together with reduced antioxidative defense pathways. These results reveal metabolic re-programming in intestinal cells under UC, showing dysregulation in all four major metabolic pathways. Our study underscores the importance of metabolic drivers in the pathogenesis of IBD and suggests that the modification of metabolism may serve as a novel diagnostic/therapeutic approach for IBD.

Keywords:  TCA cycle; antioxidative defense; glycolysis; inflammatory bowel disease; metabolism; oxidative stress; proteomics; ulcerative colitis; β-oxidation

DOI:  https://doi.org/10.3390/metabo14040194
Antioxidants (Basel). 2024 Mar 27. pii: 400. [Epub ahead of print]13(4):

Glutathione Induces Keap1 S-Glutathionylation and Mitigates Oscillating Glucose-Induced β-Cell Dysfunction by Activating Nrf2.

Xiufang Chen, Qian Zhou, Huamin Chen, Juan Bai, Ruike An, Keyi Zhang, Xinyue Zhang, Hui An, Jitai Zhang, Yongyu Wang, Ming Li.

  Glutathione (GSH), a robust endogenous antioxidant, actively participates in the modulation of the redox status of cysteine residues in proteins. Previous studies have indicated that GSH can prevent β-cell failure and prediabetes caused by chronic oscillating glucose (OsG) administration. However, the precise mechanism underlying the protective effect is not well understood. Our current research reveals that GSH is capable of reversing the reduction in Nrf2 levels, as well as downstream genes Grx1 and HO-1, in the islet β-cells of rats induced by chronic OsG. In vitro experiments have further demonstrated that GSH can prevent β-cell dedifferentiation, apoptosis, and impaired insulin secretion caused by OsG. Additionally, GSH facilitates the translocation of Nrf2 into the nucleus, resulting in an upregulation of Nrf2-targeted genes such as GCLC, Grx1, HO-1, and NQO1. Notably, when the Nrf2 inhibitor ML385 is employed, the effects of GSH on OsG-treated β-cells are abrogated. Moreover, GSH enhances the S-glutathionylation of Keap1 at Cys273 and Cys288, but not Cys151, in OsG-treated β-cells, leading to the dissociation of Nrf2 from Keap1 and facilitating Nrf2 nuclear translocation. In conclusion, the protective role of GSH against OsG-induced β-cell failure can be partially attributed to its capacity to enhance Keap1 S-glutathionylation, thereby activating the Nrf2 signaling pathway. These findings provide novel insights into the prevention and treatment of β-cell failure in the context of prediabetes/diabetes, highlighting the potential of GSH.

Keywords:  Keap1; Nrf2; S-glutathionylation; glucotoxicity; glutathione; prediabetes; β-cell

DOI:  https://doi.org/10.3390/antiox13040400