bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2024‒08‒11
seventeen papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Emerging roles of the chromatin remodeler MORC2 in cancer metabolism.
  2. Synergistic Effects of Glutamine Deprivation and Metformin in Acute Myeloid Leukemia.
  3. ROLE OF L-GLUTAMINE IN THE REGULATION OF RAT SERTOLI CELL PROLIFERATION BY FSH.
  4. Glutamine withdrawal leads to the preferential activation of lipid metabolism in metastatic colorectal cancer.
  5. Integrated machine learning screened glutamine metabolism-associated biomarker SLC1A5 to predict immunotherapy response in hepatocellular carcinoma.
  6. Disrupting YAP1-mediated glutamine metabolism induces synthetic lethality alongside ODC1 inhibition in osteosarcoma.
  7. Understanding natural isotopic variations in cultured cancer cells.
  8. Glutamine is the only amino acid that can adequately support the generation of NADPH in rod photoreceptors.
  9. Epigenetic repression of de novo cysteine synthetases induces intra-cellular accumulation of cysteine in hepatocarcinoma by up-regulating the cystine uptake transporter xCT.
  10. Regulation of cancer cell lipid metabolism and oxidative phosphorylation by microenvironmental acidosis.
  11. Hierarchical tricarboxylic acid cycle regulation by hepatocyte arginase 2 links the urea cycle to oxidative metabolism.
  12. Integrated analysis of disulfidoptosis-related genes identifies NRP1 as a novel biomarker promoting proliferation of gastric cancer via glutamine mediated energy metabolism.
  13. Coordinating energy metabolism and signaling pathways in epithelial self-renewal and differentiation.
  14. Mitochondrial signaling pathways and their role in cancer drug resistance.
  15. Involvement of tumor immune microenvironment metabolic reprogramming in colorectal cancer progression, immune escape, and response to immunotherapy.
  16. Unlocking the potential: Targeting metabolic pathways in the tumor microenvironment for Cancer therapy.
  17. Stanniocalcin 2 governs cancer cell adaptation to nutrient insufficiency through alleviation of oxidative stress.
  1. Med Oncol. 2024 Aug 08. 41(9): 221
    Emerging roles of the chromatin remodeler MORC2 in cancer metabolism.
    Bibhukalyan Mohapatra, Suresh B Pakala.
      Cancer is characterized by metabolic reprogramming in cancer cells, which is crucial for tumorigenesis. The highly deregulated chromatin remodeler MORC2 contributes to cell proliferation, invasion, migration, DNA repair, and chemoresistance. MORC2 also plays a key role in metabolic reprogramming, including lipogenesis, glucose, and glutamine metabolism. A recent study showed that MORC2-regulated glucose metabolism affects the expression of E-cadherin, a crucial protein in the epithelial-to-mesenchymal transition. This review discusses recent developments in MORC2 regulated cancer cell metabolism and its role in cancer progression.
    Keywords:  Glucose metabolism; Glutamine metabolism; Lipogenesis; MORC2
    DOI:  https://doi.org/10.1007/s12032-024-02464-9
  2. Curr Med Sci. 2024 Aug 03.
    Synergistic Effects of Glutamine Deprivation and Metformin in Acute Myeloid Leukemia.
    Tong-Yuan Liu, Xing Fu, Ying Yang, Jia Gu, Min Xiao, Deng-Ju Li.
      OBJECTIVE: The metabolic reprogramming of acute myeloid leukemia (AML) cells is a compensatory adaptation to meet energy requirements for rapid proliferation. This study aimed to examine the synergistic effects of glutamine deprivation and metformin exposure on AML cells.METHODS: SKM-1 cells (an AML cell line) were subjected to glutamine deprivation and/or treatment with metformin or bis-2-(5-phenylacetamido-1,2,4-thiadiazol-2-yl) ethyl sulfide (BPTES, a glutaminase inhibitor) or cytarabine. Cell viability was detected by Cell Counting Kit-8 (CCK-8) assay, and cell apoptosis and reactive oxygen species (ROS) by flow cytometry. Western blotting was conducted to examine the levels of apoptotic proteins, including cleaved caspase-3 and poly(ADP-ribose) polymerase (PARP). Moreover, the human long noncoding RNA (lncRNA) microarray was used to analyze gene expression after glutamine deprivation, and results were confirmed with quantitative RT-PCR (qRT-PCR). The expression of metallothionein 2A (MT2A) was suppressed using siRNA. Cell growth and apoptosis were further detected by CCK-8 assay and flow cytometry, respectively, in cells with MT2A knockdown.
    RESULTS: Glutamine deprivation or treatment with BPTES inhibited cell growth and induced apoptosis in SKM-1 cells. The lncRNA microarray result showed that the expression of MT family genes was significantly upregulated after glutamine deprivation. MT2A knockdown increased apoptosis, while proliferation was not affected in SKM-1 cells. In addition, metformin inhibited cell growth and induced apoptosis in SKM-1 cells. Both glutamine deprivation and metformin enhanced the sensitivity of SKM-1 cells to cytarabine. Furthermore, the combination of glutamine deprivation with metformin exhibited synergistic antileukemia effects on SKM-1 cells.
    CONCLUSION: Targeting glutamine metabolism in combination with metformin is a promising new therapeutic strategy for AML.
    Keywords:  acute myeloid leukemia; glutamine; metallothionein; metformin
    DOI:  https://doi.org/10.1007/s11596-024-2913-z
  3. Reproduction. 2024 Aug 01. pii: REP-24-0177. [Epub ahead of print]
    ROLE OF L-GLUTAMINE IN THE REGULATION OF RAT SERTOLI CELL PROLIFERATION BY FSH.
    Cecilia Lucia Centola, Marina Ercilia Dasso, María Fernanda Riera, Silvina Beatriz Meroni, María Noel Galardo.
      The spermatogenic capacity of adult individuals depends on, among other factors, the number of Sertoli cells (SCs) that results from the proliferative waves during development. FSH upregulates SC proliferation at least partly, through the activation of the PI3K/Akt/mTORC1 pathway, among other mechanisms. It is widely known that mTORC1 is a sensor of amino acids. Among amino acids, glutamine acquires relevance since it might contribute to cell cycle progression through the modulation of mTORC1 activity. It has not been studied yet whether glutamine intervenes in FSH-mediated regulation of SC proliferation and cell cycle progression, or if FSH has any effect on glutamine metabolism. Eight-day-old rat SCs were incubated in culture media without glutamine or with glutamine in the absence or presence of a glutamine transporter inhibitor or a glutaminase activity inhibitor under basal conditions or stimulated with FSH. The results obtained show that FSH does not promote SC proliferation and mTORC1 activation in the absence of glutamine. Also, FSH modulates glutamine metabolism increasing Glutaminase isoform 2 and reducing Glutamine synthetase expression. FSH did not promote SC proliferation and mTORC1 activation when glutaminase activity was inhibited. The results suggest that glutamine or its metabolites might cooperate with FSH in the upregulation of SC proliferation through mTORC1. In addition, as FSH modulates glutamine metabolism through the induction of Glutaminase isoform 2, the hormonal control of glutamine metabolism might be part of the intricate signalling network triggered by FSH, which is crucial to establish the population of mature SCs that supports the reproductive function.
    DOI:  https://doi.org/10.1530/REP-24-0177
  4. Transl Oncol. 2024 Aug 06. pii: S1936-5233(24)00205-5. [Epub ahead of print]48 102078
    Glutamine withdrawal leads to the preferential activation of lipid metabolism in metastatic colorectal cancer.
    Aliye Ezgi Güleç Taşkıran, Diren Arda Karaoğlu, Cemil Can Eylem, Çağdaş Ermiş, İsmail Güderer, Emirhan Nemutlu, Seçil Demirkol Canlı, Sreeparna Banerjee.
      INTRODUCTION: Glutamine is a non-essential amino acid that is critical for cell growth. However, the differential metabolism of l-glutamine in metastatic versus primary colorectal cancer (CRC) has not been evaluated adequately.MATERIALS AND METHODS: Differential expression of glutamine-related genes was determined in primary versus metastatic CRC. Univariate Cox regression and hierarchical clustering were used to generate a gene signature for prognostication. Untargeted metabolomics and 18O based fluxomics were used to identify differential metabolite levels and energy turnover in the paired primary (SW480) and metastatic (SW620) CRC cells. Western blot and qRT-PCR were used to validate differential gene expression. Subcellular localization of E-cadherin was determined by immunocytochemistry. Lipid droplets were visualized with Nile Red.
    RESULTS: The GO term "Glutamine metabolism" was significantly enriched in metastatic versus primary tumors. Supporting this, SW620 cells showed decreased membrane localization of E-cadherin and increased motility upon l-Glutamine withdrawal. A glutamine related signature associated with worse prognosis was identified and validated in multiple datasets. A fluxomics assay revealed a slower TCA cycle in SW480 and SW620 cells upon l-Glutamine withdrawal. SW620 cells, however, could maintain high ATP levels. Untargeted metabolomics indicated the preferential metabolism of fatty acids in SW620 but not SW480 cells. Lipids were mainly obtained from the environment rather than by de novo synthesis.
    CONCLUSIONS: Metastatic CRC cells can display aberrant glutamine metabolism. We show for the first time that upon l-glutamine withdrawal, SW620 (but not SW480) cells were metabolically plastic and could metabolize lipids for survival and cellular motility.
    Keywords:  Colorectal cancer; L-Glutamine; Lipid metabolism; Metabolic plasticity
    DOI:  https://doi.org/10.1016/j.tranon.2024.102078
  5. Immunobiology. 2024 Aug 02. pii: S0171-2985(24)00059-7. [Epub ahead of print]229(5): 152841
    Integrated machine learning screened glutamine metabolism-associated biomarker SLC1A5 to predict immunotherapy response in hepatocellular carcinoma.
    Guixiong Zhang, Yitai Xiao, Hang Liu, Yanqin Wu, Miao Xue, Jiaping Li.
      Hepatocellular carcinoma (HCC) stands as one of the most prevalent malignancies. While PD-1 immune checkpoint inhibitors have demonstrated promising therapeutic efficacy in HCC, not all patients exhibit a favorable response to these treatments. Glutamine is a crucial immune cell regulatory factor, and tumor cells exhibit glutamine dependence. In this study, HCC patients were divided into two subtypes (C1 and C2) based on glutamine metabolism-related genes via consensus clustering. The C1 pattern, in contrast to C2, was associated with a lower survival probability among HCC patients. Additionally, the C1 pattern exhibited higher proportions of patients with advanced tumor stages. The activity of C1 in glutamine metabolism and transport is significantly enhanced, while its oxidative phosphorylation activity is reduced. And, C1 was mainly involved in the progression-related pathway of HCC. Furthermore, C1 exhibited high levels of immunosuppressive cells, cytokine-receptor interactions and immune checkpoint genes, suggesting C1 as an immunosuppressive subtype. After stepwise selection based on integrated four machine learning methods, SLC1A5 was finally identified as the pivotal gene that distinguishes the subtypes. The expression of SLC1A5 was significantly positively correlated with immunosuppressive status. SLC1A5 showed the most significant correlation with macrophage infiltration, and this correlation was confirmed through the RNA-seq data of CLCA project and our cohort. Low-SLC1A5-expression samples had better immunogenicity and responsiveness to immunotherapy. As expected, SubMap and survival analysis indicated that individuals with low SLC1A5 expression were more responsive to anti-PD1 therapy. Collectively, this study categorized HCC patients based on glutamine metabolism-related genes and proposed two subclasses with different clinical traits, biological behavior, and immune status. Machine learning was utilized to identify the hub gene SLC1A5 for HCC classification, which also could predict immunotherapy response.
    Keywords:  Glutamine metabolism; Hepatocellular carcinoma; Immunotherapy; Machine learning; SLC1A5
    DOI:  https://doi.org/10.1016/j.imbio.2024.152841
  6. Cell Oncol (Dordr). 2024 Aug 08.
    Disrupting YAP1-mediated glutamine metabolism induces synthetic lethality alongside ODC1 inhibition in osteosarcoma.
    Hongsheng Wang, Yining Tao, Jing Han, Jiakang Shen, Haoran Mu, Zhuoying Wang, Jinzeng Wang, Xinmeng Jin, Qi Zhang, Yuqin Yang, Jun Lin, Mengxiong Sun, Xiaojun Ma, Ling Ren, Amy K LeBlanc, Jing Xu, Yingqi Hua, Wei Sun.
      PURPOSE: Osteosarcoma, a highly malignant primary bone tumor primarily affecting adolescents, frequently develops resistance to initial chemotherapy, leading to metastasis and limited treatment options. Our study aims to uncover novel therapeutic targets for metastatic and recurrent osteosarcoma.METHODS: In this study, we proved the potential of modulating the YAP1-regulated glutamine metabolic pathway to augment the response of OS to DFMO. We initially employed single-cell transcriptomic data to gauge the activation level of polyamine metabolism in MTAP-deleted OS patients. This was further substantiated by transcriptome sequencing data from recurrent and non-recurrent patient tissues, confirming the activation of polyamine metabolism in progressive OS. Through high-throughput drug screening, we pinpointed CIL56, a YAP1 inhibitor, as a promising candidate for a combined therapeutic strategy with DFMO. In vivo, we utilized PDX and CDX models to validate the therapeutic efficacy of this drug combination. In vitro, we conducted western blot analysis, qPCR analysis, immunofluorescence staining, and PuMA experiments to monitor alterations in molecular expression, distribution, and tumor metastasis capability. We employed CCK-8 and colony formation assays to assess the proliferative capacity of cells in the experimental group. We used flow cytometry and reactive oxygen probes to observe changes in ROS and glutamine metabolism within the cells. Finally, we applied RNA-seq in tandem with metabolomics to identify metabolic alterations in OS cells treated with a DFMO and CIL56 combination. This enabled us to intervene and validate the role of the YAP1-mediated glutamine metabolic pathway in DFMO resistance.
    RESULTS: Through single-cell RNA-seq data analysis, we pinpointed a subset of late-stage OS cells with significantly upregulated polyamine metabolism. This upregulation was further substantiated by transcriptomic profiling of recurrent and non-recurrent OS tissues. High-throughput drug screening revealed a promising combination strategy involving DFMO and CIL56. DFMO treatment curbs the phosphorylation of YAP1 protein in OS cells, promoting nuclear entry and initiating the YAP1-mediated glutamine metabolic pathway. This reduces intracellular ROS levels, countering DFMO's anticancer effect. The therapeutic efficacy of DFMO can be amplified both in vivo and in vitro by combining it with the YAP1 inhibitor CIL56 or the glutaminase inhibitor CB-839. This underscores the significant potential of targeting the YAP1-mediated glutamine metabolic pathway to enhance efficacy of DFMO.
    CONCLUSION: Our findings elucidate YAP1-mediated glutamine metabolism as a crucial bypass mechanism against DFMO, following the inhibition of polyamine metabolism. Our study provides valuable insights into the potential role of DFMO in an "One-two Punch" therapy of metastatic and recurrent osteosarcoma.
    Keywords:  Glutamine metabolism; High-throughput drug screening; Osteosarcoma; Polyamine metabolism; Single-cell RNA-seq; YAP1
    DOI:  https://doi.org/10.1007/s13402-024-00967-1
  7. Rapid Commun Mass Spectrom. 2024 Oct 15. 38(19): e9878
    Understanding natural isotopic variations in cultured cancer cells.
    Olivier L Mantha, Marie Mahé, Karine Mahéo, Gaëlle Fromont, Maxime Guéguinou, Illa Tea, Régis Hankard, Arnaud De Luca.
      RATIONALE: Natural variations in the abundance of the stable isotopes of nitrogen (δ15N) and carbon (δ13C) offer valuable insights into metabolic fluxes. In the wake of strong interest in cancer metabolism, recent research has revealed δ15N and δ13C variations in cancerous compared to non-cancerous tissues and cell lines. However, our understanding of natural isotopic variations in cultured mammalian cells, particularly in relation to metabolism, remains limited. This study aims to start addressing this gap using metabolic modulations in cells cultured under controlled conditions.METHODS: Prostate cancer cells (PC3) were cultured in different conditions and their δ15N and δ13C were measured using isotope ratio mass spectrometry. Isotopic variations during successive cell culture passages were assessed and two widely used cell culture media (RPMI and DMEM) were compared. Metabolism was modulated through glutamine deprivation and hypoxia.
    RESULTS: Successive cell culture passages generally resulted in reproducible δ15N and δ13C values. The impact of culture medium composition on δ15N and δ13C of the cells highlights the importance of maintaining a consistent medium composition across conditions whenever possible. Glutamine deprivation and hypoxia induced a lower δ13C in bulk cell samples, with only the former affecting δ15N. Gaps between theory and experiments were bridged and the lessons learned throughout the process are provided.
    CONCLUSIONS: Exposing cultured cancer cells to hypoxia allowed us to further investigate the relation between metabolic modulations and natural isotopic variations, while mitigating the confounding impact of changing culture medium composition. This study highlights the potential of natural δ13C variations for studying substrate fluxes and nutrient allocation in reproducible culture conditions. Considering cell yield and culture medium composition is pivotal to the success of this approach.
    DOI:  https://doi.org/10.1002/rcm.9878
  8. Exp Eye Res. 2024 Aug 05. pii: S0014-4835(24)00239-2. [Epub ahead of print]246 110018
    Glutamine is the only amino acid that can adequately support the generation of NADPH in rod photoreceptors.
    Leopold Adler, Chunhe Chen, Yiannis Koutalos.
      NADPH, the primary source of reducing equivalents in the cytosol, is used in vertebrate rod photoreceptor outer segments to reduce the all-trans retinal released from photoactivated visual pigment to all-trans retinol. Light activation of the visual pigment isomerizes the 11-cis retinal chromophore to all-trans, thereby destroying it and necessitating its regeneration. Release and reduction of all-trans retinal are the first steps in the series of reactions that regenerate the visual pigment. Glucose and glutamine can both support the reduction of all-trans retinal to retinol, indicating that the NADPH used in rod photoreceptor outer segments can be generated by the pentose phosphate pathway as well as by mitochondria-linked pathways. We have used the conversion of all-trans retinal to all-trans retinol to examine whether amino acids other than glutamine can also support the generation of NADPH in rod photoreceptors. We have measured this conversion in single isolated mouse rod photoreceptors by imaging the fluorescence of the all-trans retinal and retinol generated after exposure of the cells to light. In agreement with previous work, we find that 5 mM glucose or 0.5 mM glutamine support the conversion of ∼70-80% of all-trans retinal to retinol, corresponding to a reduced NADP fraction of ∼10%. All other amino acids at 0.5 mM concentration support the conversion to a much lesser extent, indicating reduced NADP fractions of 1-2% at most. Taurine was also ineffective at supporting NADPH generation, while formic acid, the toxic metabolite of methanol, suppressed the generation of NADPH by either glucose or glutamine.
    Keywords:  Amino acids; Mitochondria; NADPH; Photoreceptor; Retinal; Retinol
    DOI:  https://doi.org/10.1016/j.exer.2024.110018
  9. Cancer Metab. 2024 Aug 07. 12(1): 23
    Epigenetic repression of de novo cysteine synthetases induces intra-cellular accumulation of cysteine in hepatocarcinoma by up-regulating the cystine uptake transporter xCT.
    Tomoaki Yamauchi, Yumi Okano, Daishu Terada, Sai Yasukochi, Akito Tsuruta, Yuya Tsurudome, Kentaro Ushijima, Naoya Matsunaga, Satoru Koyanagi, Shigehiro Ohdo.
      BACKGROUND: The metabolic reprogramming of amino acids is critical for cancer cell growth and survival. Notably, intracellular accumulation of cysteine is often observed in various cancers, suggesting its potential role in alleviating the oxidative stress associated with rapid proliferation. The liver is the primary organ for cysteine biosynthesis, but much remains unknown about the metabolic alterations of cysteine and their mechanisms in hepatocellular carcinoma cells.METHODS: RNA-seq data from patients with hepatocarcinoma were analyzed using the TNMplot database. The underlying mechanism of the oncogenic alteration of cysteine metabolism was studied in mice implanted with BNL 1ME A.7 R.1 hepatocarcinoma.
    RESULTS: Database analysis of patients with hepatocellular carcinoma revealed that the expression of enzymes involved in de novo cysteine synthesis was down-regulated accompanying with increased expression of the cystine uptake transporter xCT. Similar alterations in gene expression have also been observed in a syngeneic mouse model of hepatocarcinoma. The enhanced expression of DNA methyltransferase in murine hepatocarcinoma cells caused methylation of the upstream regions of cysteine synthesis genes, thereby repressing their expression. Conversely, suppression of de novo cysteine synthesis in healthy liver cells induced xCT expression by up-regulating the oxidative-stress response factor NRF2, indicating that reduced de novo cysteine synthesis repulsively increases cystine uptake via enhanced xCT expression, leading to intracellular cysteine accumulation. Furthermore, the pharmacological inhibition of xCT activity decreased intracellular cysteine levels and suppressed hepatocarcinoma tumor growth in mice.
    CONCLUSIONS: Our findings indicate an underlying mechanism of the oncogenic alteration of cysteine metabolism in hepatocarcinoma and highlight the efficacy of alteration of cysteine metabolism as a viable therapeutic target in cancer.
    Keywords:  Cysteine metabolism; DNA methylation; Erastin; Hepatocarcinoma; NRF2; de novo cysteine synthesis; xCT
    DOI:  https://doi.org/10.1186/s40170-024-00352-4
  10. Am J Physiol Cell Physiol. 2024 Aug 05.
    Regulation of cancer cell lipid metabolism and oxidative phosphorylation by microenvironmental acidosis.
    Michala G Rolver, Marc Severin, Stine F Pedersen.
      The expansion of cancer cell mass in solid tumors generates a harsh environment characterized by dynamically varying levels of acidosis, hypoxia and nutrient deprivation. Because acidosis inhibits glycolytic metabolism and hypoxia inhibits oxidative phosphorylation, cancer cells that survive and grow in these environments must rewire their metabolism and develop a high degree of metabolic plasticity to meet their energetic and biosynthetic demands. Cancer cells frequently upregulate pathways enabling the uptake and utilization of lipids and other nutrients derived from dead or recruited stromal cells, and in particular lipid uptake is strongly enhanced in acidic microenvironments. The resulting lipid accumulation and increased reliance on β-oxidation and mitochondrial metabolism increases susceptibility to oxidative stress, lipotoxicity and ferroptosis, in turn driving changes that may mitigate such risks. The spatially and temporally heterogeneous tumor microenvironment thus selects for invasive, metabolically flexible, and resilient cancer cells capable of exploiting their local conditions as well as of seeking out more favorable surroundings. This phenotype relies on the interplay between metabolism, acidosis and oncogenic mutations, driving metabolic signaling pathways such as peroxisome proliferator-activated receptors (PPARs). Understanding the particular vulnerabilities of such cells may uncover novel therapeutic liabilities of the most aggressive cancer cells.
    Keywords:  ferroptosis; lipid metabolism; mitochondria; oxidative phosphorylation; peroxisomes
    DOI:  https://doi.org/10.1152/ajpcell.00429.2024
  11. Cell Metab. 2024 Aug 01. pii: S1550-4131(24)00278-X. [Epub ahead of print]
    Hierarchical tricarboxylic acid cycle regulation by hepatocyte arginase 2 links the urea cycle to oxidative metabolism.
    Yiming Zhang, Cassandra B Higgins, Stefani Tica, Joshua A Adams, Jiameng Sun, Shannon C Kelly, Xiaoyu Zong, Dennis J Dietzen, Terri Pietka, Samuel J Ballentine, Leah Shriver, Gary Patti, Yin Cao, Brian J DeBosch.
      Urea cycle impairment and its relationship to obesity and inflammation remained elusive, partly due to the dramatic clinical presentation of classical urea cycle defects. We generated mice with hepatocyte-specific arginase 2 deletion (Arg2LKO) and revealed a mild compensated urea cycle defect. Stable isotope tracing and respirometry revealed hepatocyte urea and TCA cycle flux defects, impaired mitochondrial oxidative metabolism, and glutamine anaplerosis despite normal energy and glucose homeostasis during early adulthood. Yet during middle adulthood, chow- and diet-induced obese Arg2LKO mice develop exaggerated glucose and lipid derangements, which are reversible by replacing the TCA cycle oxidative substrate nicotinamide adenine dinucleotide. Moreover, serum-based hallmarks of urea, TCA cycle, and mitochondrial derangements predict incident fibroinflammatory liver disease in 106,606 patients nearly a decade in advance. The data reveal hierarchical urea-TCA cycle control via ARG2 to drive oxidative metabolism. Moreover, perturbations in this circuit may causally link urea cycle compromise to fibroinflammatory liver disease.
    Keywords:  arginase; diabetes; fasting; metabolic dysfunction-associated steatohepatitis; metabolic dysfunction-associated steatotic liver disease; nicotinamide adenine dinucleotide; nicotinamide riboside; obesity; tricarboxylic acid cycle; urea cycle
    DOI:  https://doi.org/10.1016/j.cmet.2024.07.007
  12. Discov Oncol. 2024 Aug 07. 15(1): 337
    Integrated analysis of disulfidoptosis-related genes identifies NRP1 as a novel biomarker promoting proliferation of gastric cancer via glutamine mediated energy metabolism.
    Qiuhua Li, Guofeng Shi, Yuebo Li, Ren Lu, Zhaozhe Liu.
      The incidence and mortality of gastric cancer rank fifth and fourth worldwide among all malignancies, respectively. Additionally, disulfidoptosis, a recently identified form of cellular demise, is closely linked to the initiation and advancement of malignancies. This study aims to create a novel signature of disulfidptosis-related genes (DRGs) and to further explore its association with the tumor immune microenvironment. Based on our comprehensive study, a prognostic signature consisting of 31 DRGs in stomach adenocarcinoma (STAD) was identified and characterized. Through the integrative analyses involving gene expression profiling, machine learning algorithms, and Cox regression models, the prognostic significance of these DRGs was demonstrated. Our findings highlight their strong predictive power in assessing overall survival across diverse patient datasets, and their better performance than traditional clinicopathological factors. Moreover, the DRGs signature showed association with the characteristics of the tumor microenvironment, which has implications for the immune modulation and therapeutic strategies in STAD. Specifically, NRP1 emerged as a key DRG with elevated expression in STAD, showing correlation with the advanced stages of diseases and poorer outcomes. Functional studies further revealed the role of NRP1 in promoting STAD cell proliferation through the modulation of glutamine metabolism. Overall, our study underscores the clinical relevance of DRGs as biomarker and potential therapeutic targets in STAD management, providing insights into disease biology and personalized treatments.
    Keywords:  Disulfidptosis-related genes; Glutamine mediated energy metabolism; NRP1; Prognosis; Stomach adenocarcinoma
    DOI:  https://doi.org/10.1007/s12672-024-01217-4
  13. Biol Direct. 2024 Aug 07. 19(1): 63
    Coordinating energy metabolism and signaling pathways in epithelial self-renewal and differentiation.
    Maria Pia Polito, Alessio Romaldini, Serena Rinaldo, Elena Enzo.
      Epidermal stem cells (EPSCs) are essential for maintaining skin homeostasis and ensuring a proper wound healing. During in vitro cultivations, EPSCs give rise to transient amplifying progenitors and differentiated cells, finally forming a stratified epithelium that can be grafted onto patients. Epithelial grafts have been used in clinics to cure burned patients or patients affected by genetic diseases. The long-term success of these advanced therapies relies on the presence of a correct amount of EPSCs that guarantees long-term epithelial regeneration. For this reason, a deeper understanding of self-renewal and differentiation is fundamental to fostering their clinical applications.The coordination between energetic metabolism (e.g., glycolysis, tricarboxylic acid cycle, oxidative phosphorylation, and amino acid synthesis pathways), molecular signalling pathways (e.g., p63, YAP, FOXM1, AMPK/mTOR), and epigenetic modifications controls fundamental biological processes as proliferation, self-renewal, and differentiation. This review explores how these signalling and metabolic pathways are interconnected in the epithelial cells, highlighting the distinct metabolic demands and regulatory mechanisms involved in skin physiology.
    Keywords:  Epidermal stem cells; Metabolism; Signaling pathways
    DOI:  https://doi.org/10.1186/s13062-024-00510-0
  14. Cell Signal. 2024 Aug 05. pii: S0898-6568(24)00297-3. [Epub ahead of print]122 111329
    Mitochondrial signaling pathways and their role in cancer drug resistance.
    Ashwani Sharma, Tarun Virmani, Girish Kumar, Anjali Sharma, Reshu Virmani, Dalapathi Gugulothu, Kuldeep Singh, Shashi Kiran Misra, Kamla Pathak, Nitin Chitranshi, Henrique Douglas Melo Coutinho, Divya Jain.
      Mitochondria, traditionally known as cellular powerhouses, now emerge as critical signaling centers influencing cancer progression and drug resistance. The review highlights the role that apoptotic signaling, DNA mutations, mitochondrial dynamics and metabolism play in the development of resistance mechanisms and the advancement of cancer. Targeted approaches are discussed, with an emphasis on managing mitophagy, fusion, and fission of the mitochondria to make resistant cancer cells more susceptible to traditional treatments. Additionally, metabolic reprogramming can be used to effectively target metabolic enzymes such GLUT1, HKII, PDK, and PKM2 in order to avoid resistance mechanisms. Although there are potential possibilities for therapy, the complex structure of mitochondria and their subtle role in tumor development hamper clinical translation. Novel targeted medicines are put forth, providing fresh insights on combating drug resistance in cancer. The study also emphasizes the significance of glutamine metabolism, mitochondrial respiratory complexes, and apoptotic pathways as potential targets to improve treatment effectiveness against drug-resistant cancers. Combining complementary and nanoparticle-based techniques to target mitochondria has demonstrated encouraging results in the treatment of cancer, opening doors to reduce resistance and enable individualized treatment plans catered to the unique characteristics of each patient. Suggesting innovative approaches such as drug repositioning and mitochondrial drug delivery to enhance the efficacy of mitochondria-targeting therapies, presenting a pathway for advancements in cancer treatment. This thorough investigation is a major step forward in the treatment of cancer and has the potential to influence clinical practice and enhance patient outcomes.
    Keywords:  Apoptosis; Biological signaling cascades; Cancer drug resistance; Metastatic activities; Mitochondria; Mitochondrial signaling pathways
    DOI:  https://doi.org/10.1016/j.cellsig.2024.111329
  15. Front Immunol. 2024 ;15 1353787
    Involvement of tumor immune microenvironment metabolic reprogramming in colorectal cancer progression, immune escape, and response to immunotherapy.
    Andrea Nicolini, Paola Ferrari.
      Metabolic reprogramming is a k`ey hallmark of tumors, developed in response to hypoxia and nutrient deficiency during tumor progression. In both cancer and immune cells, there is a metabolic shift from oxidative phosphorylation (OXPHOS) to aerobic glycolysis, also known as the Warburg effect, which then leads to lactate acidification, increased lipid synthesis, and glutaminolysis. This reprogramming facilitates tumor immune evasion and, within the tumor microenvironment (TME), cancer and immune cells collaborate to create a suppressive tumor immune microenvironment (TIME). The growing interest in the metabolic reprogramming of the TME, particularly its significance in colorectal cancer (CRC)-one of the most prevalent cancers-has prompted us to explore this topic. CRC exhibits abnormal glycolysis, glutaminolysis, and increased lipid synthesis. Acidosis in CRC cells hampers the activity of anti-tumor immune cells and inhibits the phagocytosis of tumor-associated macrophages (TAMs), while nutrient deficiency promotes the development of regulatory T cells (Tregs) and M2-like macrophages. In CRC cells, activation of G-protein coupled receptor 81 (GPR81) signaling leads to overexpression of programmed death-ligand 1 (PD-L1) and reduces the antigen presentation capability of dendritic cells. Moreover, the genetic and epigenetic cell phenotype, along with the microbiota, significantly influence CRC metabolic reprogramming. Activating RAS mutations and overexpression of epidermal growth factor receptor (EGFR) occur in approximately 50% and 80% of patients, respectively, stimulating glycolysis and increasing levels of hypoxia-inducible factor 1 alpha (HIF-1α) and MYC proteins. Certain bacteria produce short-chain fatty acids (SCFAs), which activate CD8+ cells and genes involved in antigen processing and presentation, while other mechanisms support pro-tumor activities. The use of immune checkpoint inhibitors (ICIs) in selected CRC patients has shown promise, and the combination of these with drugs that inhibit aerobic glycolysis is currently being intensively researched to enhance the efficacy of immunotherapy.
    Keywords:  colorectal cancer; immunotherapy; metabolic reprogramming; tumor immune escape; tumor immune microenvironment
    DOI:  https://doi.org/10.3389/fimmu.2024.1353787
  16. Biochim Biophys Acta Rev Cancer. 2024 Aug 05. pii: S0304-419X(24)00097-0. [Epub ahead of print] 189166
    Unlocking the potential: Targeting metabolic pathways in the tumor microenvironment for Cancer therapy.
    Siyuan Jia, Ann M Bode, Xue Chen, Xiangjian Luo.
      Cancer incidence and mortality are increasing and impacting global life expectancy. Metabolic reprogramming in the tumor microenvironment (TME) is intimately related to tumorigenesis, progression, metastasis and drug resistance. Tumor cells drive metabolic reprogramming of other cells in the TME through metabolic induction of cytokines and metabolites, and metabolic substrate competition. Consequently, this boosts tumor cell growth by providing metabolic support and facilitating immunosuppression and angiogenesis. The metabolic interplay in the TME presents potential therapeutic targets. Here, we focus on the metabolic reprogramming of four principal cell subsets in the TME: CAFs, TAMs, TILs and TECs, and their interaction with tumor cells. We also summarize medications and therapies targeting these cells' metabolic pathways, particularly in the context of immune checkpoint blockade therapy.
    Keywords:  Cancer-associated fibroblasts (CAFs); Immune check point blockade (ICB); Metabolic reprogramming; Tumor endothelial cells (TECs); Tumor microenvironment (TME); Tumor-associated macrophages (TAMs); Tumor-infiltrating lymphocytes (TILs) therapy
    DOI:  https://doi.org/10.1016/j.bbcan.2024.189166
  17. Cell Death Dis. 2024 Aug 06. 15(8): 567
    Stanniocalcin 2 governs cancer cell adaptation to nutrient insufficiency through alleviation of oxidative stress.
    Shuo Qie, Haijuan Xiong, Yaqi Liu, Chenhui Yan, Yalei Wang, Lifeng Tian, Chenguang Wang, Nianli Sang.
      Solid tumours often endure nutrient insufficiency during progression. How tumour cells adapt to temporal and spatial nutrient insufficiency remains unclear. We previously identified STC2 as one of the most upregulated genes in cells exposed to nutrient insufficiency by transcriptome screening, indicating the potential of STC2 in cellular adaptation to nutrient insufficiency. However, the molecular mechanisms underlying STC2 induction by nutrient insufficiency and subsequent adaptation remain elusive. Here, we report that STC2 protein is dramatically increased and secreted into the culture media by Gln-/Glc- deprivation. STC2 promoter contains cis-elements that are activated by ATF4 and p65/RelA, two transcription factors activated by a variety of cellular stress. Biologically, STC2 induction and secretion promote cell survival but attenuate cell proliferation during nutrient insufficiency, thus switching the priority of cancer cells from proliferation to survival. Loss of STC2 impairs tumour growth by inducing both apoptosis and necrosis in mouse xenografts. Mechanistically, under nutrient insufficient conditions, cells have increased levels of reactive oxygen species (ROS), and lack of STC2 further elevates ROS levels that lead to increased apoptosis. RNA-Seq analyses reveal STC2 induction suppresses the expression of monoamine oxidase B (MAOB), a mitochondrial membrane enzyme that produces ROS. Moreover, a negative correlation between STC2 and MAOB levels is also identified in human tumour samples. Importantly, the administration of recombinant STC2 to the culture media effectively suppresses MAOB expression as well as apoptosis, suggesting STC2 functions in an autocrine/paracrine manner. Taken together, our findings indicate that nutrient insufficiency induces STC2 expression, which in turn governs the adaptation of cancer cells to nutrient insufficiency through the maintenance of redox homoeostasis, highlighting the potential of STC2 as a therapeutic target for cancer treatment.
    DOI:  https://doi.org/10.1038/s41419-024-06961-7
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