bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2022–04–17
thirteen papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. Ag120-Mediated Inhibition of ASCT2-Dependent Glutamine Transport has an Anti-Tumor Effect on Colorectal Cancer Cells.
  2. Discovery of novel glutaminase 1 allosteric inhibitor with 4-piperidinamine linker and aromatic heterocycles.
  3. Progress in Metabolic Studies of Gastric Cancer and Therapeutic Implications.
  4. Osmundacetone modulates mitochondrial metabolism in non-small cell lung cancer cells by hijacking the glutamine/glutamate/α-KG metabolic axis.
  5. Conversion of Hyperpolarized [1-13C]Pyruvate in Breast Cancer Cells Depends on Their Malignancy, Metabolic Program and Nutrient Microenvironment.
  6. Ketogenic diet and chemotherapy combine to disrupt pancreatic cancer metabolism and growth.
  7. Mitochondrial calcium uniporter drives metastasis and confers a targetable cystine dependency in pancreatic cancer.
  8. A Rational Foundation for Micheliolide-based Combination Strategy by Targeting Redox and Metabolic Circuit in Cancer Cells.
  9. Estrogens and Progestins Cooperatively Shift Breast Cancer Cell Metabolism.
  10. Development of Optical Biosensor for the Detection of Glutamine in Human Biofluids Using Merocyanine Dye.
  11. Integrative proteomics and metabolomics approach to elucidate metabolic dysfunction induced by silica nanoparticles in hepatocytes.
  12. Pyruvate Dehydrogenase Kinase Inhibition by Dichloroacetate in Melanoma Cells Unveils Metabolic Vulnerabilities.
  13. SENP1-Sirt3 signaling promotes α-ketoglutarate production during M2 macrophage polarization.
  1. Front Pharmacol. 2022 ;13 871392
    Ag120-Mediated Inhibition of ASCT2-Dependent Glutamine Transport has an Anti-Tumor Effect on Colorectal Cancer Cells.
    Wei Yu, Jianwen Huang, Qichao Dong, Wenting Li, Lei Jiang, Qian Zhang, Li Sun, Shengtao Yuan, Xu He.
      Metabolic reprogramming is considered to be a hallmark of cancer, and increased glutamine metabolism plays an important role in the progression of many tumors, including colorectal cancer (CRC). Targeting of glutamine uptake via the transporter protein ASCT2/SLC1A5 (solute carrier family 1 member 5) is considered to be an effective strategy for the treatment of malignant tumors. Here, we demonstrate that Ag120 (ivosidenib), a mutant isocitrate dehydrogenase 1 (IDH1) inhibitor approved for the treatment of certain cancers, acts as an ASCT2 inhibitor in CRC cells. Ag120 blocked glutamine uptake and metabolism, leading to reduced cell proliferation, elevated autophagy, and increased oxidative stress in CRC cells in vitro and in vivo, potentially via the ERK and mTOR signaling pathways. These effects occurred independently of mutant IDH1 activity and were supported by experiments with ASCT2-depleted or -overexpressing cells. These data identify a novel mechanism of Ag120 anti-tumor activity and support further exploration of ASCT2 inhibitors for cancer therapy.
    Keywords:  AG120; ASCT2; CRC; glutamine metabolism; tumor proliferation
    DOI:  https://doi.org/10.3389/fphar.2022.871392
  2. Eur J Med Chem. 2022 Apr 06. pii: S0223-5234(22)00239-2. [Epub ahead of print]236 114337
    Discovery of novel glutaminase 1 allosteric inhibitor with 4-piperidinamine linker and aromatic heterocycles.
    Xi Xu, Xiujin Chang, Jingxuan Huang, Di Zhang, Min Wang, Tian Jing, Yu Zhuang, Junping Kou, Zhixia Qiu, Jubo Wang, Zhiyu Li, Jinlei Bian.
      Glutaminase 1 (GLS1) is overexpressed in multiple types of malignant tumors and is viewed as a promising target in cancer therapy. Thus, the discovery for small-molecule GLS1 inhibitors is being urgent. Based on our previous study of C147, a potent GLS1 allosteric inhibitor yet with a limited metabolic stability, a structure-based optimization was carried out, with a series of novel GLS1 allosteric inhibitors rationally designed, synthesized and biologically evaluated. Such endeavor has culminated in the identification of 41e, a promising GLS1 allosteric inhibitor with 4-piperidinamine linker and aromatic heterocycles. 41e displayed robust GLS1 binding affinity, superior liver microsome metabolic stability, and moderate anti-tumor activity (TGI: 47.5%) in HCT116 xenograft model with no considerable toxicity in vivo. The mechanism underlying the anti-proliferative effect of 41e on HCT116 cells was studied, revealing that the compound blocked the glutamine metabolism, induced the production of ROS, and triggered apoptosis. These findings merit further investigation of 41e as a targeted cancer therapeutic.
    Keywords:  4-Piperidinamine; Allosteric inhibitors; GLS1; Glutaminase 1; Glutamine metabolism
    DOI:  https://doi.org/10.1016/j.ejmech.2022.114337
  3. Curr Cancer Drug Targets. 2022 Apr 13.
    Progress in Metabolic Studies of Gastric Cancer and Therapeutic Implications.
    Adriana Romo-Perez, Guadalupe Dominguez-Gomez, Alma Chavez-Blanco, Lucia Taja-Chayeb, Aurora Gonzalez-Fierro, Consuelo Diaz-Romero, Horacio Noe Lopez-Basave, Alfonso Duenas-Gonzalez.
       BACKGROUND: Worldwide, gastric cancer is ranked the fifth malignancy in incidence and the third malignancy in mortality. Gastric cancer causes an altered metabolism that can be therapeutically exploited.
    OBJECTIVE: To provide an overview of the significant metabolic alterations caused by gastric cancer and propose a blockade.
    METHODS: A comprehensive and up-to-date review of descriptive and experimental publications on the metabolic alterations caused by gastric cancer and their blockade. This is not a systematic review.
    RESULTS: Gastric cancer causes high rates of glycolysis and glutaminolysis. There are increased rates of de novo fatty acid synthesis and cholesterol synthesis. Moreover, gastric cancer causes high rates of lipid turnover via fatty acid -oxidation. Preclinical data indicate that the individual blockade of these pathways via enzyme targeting leads to antitumor effects in vitro and in vivo. Nevertheless, there is no data on the simultaneous blockade of these five pathways, which is critical, as tumors show metabolic flexibility in response to the availability of nutrients. This means tumors may activate alternate routes when one or more are inhibited. We hypothesize there is a need to simultaneously blockade them to avoid or decrease the metabolic flexibility that may lead to treatment resistance.
    CONCLUSIONS: There is a need to explore the preclinical efficacy and feasibility of combined metabolic therapy targeting the pathways of glucose, glutamine, fatty acid synthesis, cholesterol synthesis, and fatty acid oxidation. This may have therapeutical implications because we have clinically available drugs that target these pathways in gastric cancer.
    Keywords:  Gastric cancer; glutaminolysis; glycolysis; lipidic; metabolic blockade; metabolism
    DOI:  https://doi.org/10.2174/1568009622666220413083534
  4. Phytomedicine. 2022 Apr 04. pii: S0944-7113(22)00153-2. [Epub ahead of print]100 154075
    Osmundacetone modulates mitochondrial metabolism in non-small cell lung cancer cells by hijacking the glutamine/glutamate/α-KG metabolic axis.
    Yue Yang, Pingya He, Yuhao Hou, Zhicheng Liu, Xiaoping Zhang, Ning Li.
       BACKGROUND: Osmundacetone (OSC) is a bioactive phenolic compound isolated from Phellinus igniarius and that was shown to exert cytotoxic effects on cancer cells in our previous work. The antiproliferative impact of OSC on non-small cell lung cancer (NSCLC) and the underlying mechanisms, however, have not been studied.
    PURPOSE: This study aimed to explore the antiproliferative effect of OSC on NSCLC cells and the mechanisms involved.
    METHODS: Cell viability, colony formation and cell cycle distribution were measured following exposure to OSC in vitro. The anticancer activity of OSC was also examined using a xenograft growth assay in vivo. Furthermore, serum metabolomics analysis by GC-MS was done to detect alterations in the metabolic profile. Next, expression of GLS1 and GLUD1, the key enzymes in glutamine metabolism, was evaluated using RT-PCR and western blot. α-KG and NADH metabolites were assessed by ELISA. Mitochondrial functions and morphology were evaluated using the JC-1 probe and transmission electron microscopy, respectively. The ATP production rate in mitochondria of cells with OSC treatment was determined using a Seahorse XFe24 Analyzer.
    RESULTS: OSC selectively reduced the proliferation of A549 and H460 cells. OSC triggered G2/M cell cycle arrest and decreased the cell clone formation. A mouse xenograft model revealed that OSC inhibited tumor growth in vivo. Findings of serum metabolomics analyses indicated that the anticancer function of OSC was related to disorders of glutamine metabolism. Such a speculation was further verified by the expression level of GLUD1, which was downregulated by OSC treatment. Concentrations of the related metabolites α-KG and NADH were reduced in response to OSC treatment. Moreover, OSC led to disorganization of the mitochondrial ultrastructure and a decrease in mitochondrial membrane potential. OSC also decreased ATP production via oxidative phosphorylation (OXPHOS) but did not affect glycolysis in NSCLC cells.
    CONCLUSION: The key role of OSC in mitochondrial energy metabolism in NSCLC cells is to suppress tumor development and cell proliferation downregulating GLUD1 to inhibit the glutamine/glutamate/α-KG metabolic axis and OXPHOS. It indicats that OSC might be a potential natural agent for personalized medicine and an anticancer metabolic modulator in NSCLC chemotherapy.
    Keywords:  Abbreviations: α-KG, α-ketoglutaric acid; Antiproliferation; Glud1; Glutamine metabolism; Nsclc; Osmundacetone
    DOI:  https://doi.org/10.1016/j.phymed.2022.154075
  5. Cancers (Basel). 2022 Apr 06. pii: 1845. [Epub ahead of print]14(7):
    Conversion of Hyperpolarized [1-13C]Pyruvate in Breast Cancer Cells Depends on Their Malignancy, Metabolic Program and Nutrient Microenvironment.
    Martin Grashei, Philipp Biechl, Franz Schilling, Angela M Otto.
      Hyperpolarized magnetic resonance spectroscopy (MRS) is a technology for characterizing tumors in vivo based on their metabolic activities. The conversion rates (kpl) of hyperpolarized [1-13C]pyruvate to [1-13C]lactate depend on monocarboxylate transporters (MCT) and lactate dehydrogenase (LDH); these are also indicators of tumor malignancy. An unresolved issue is how glucose and glutamine availability in the tumor microenvironment affects metabolic characteristics of the cancer and how this relates to kpl-values. Two breast cancer cells of different malignancy (MCF-7, MDA-MB-231) were cultured in media containing defined combinations of low glucose (1 mM; 2.5 mM) and glutamine (0.1 mM; 1 mM) and analyzed for pyruvate uptake, intracellular metabolite levels, LDH and pyruvate kinase activities, and 13C6-glucose-derived metabolomics. The results show variability of kpl with the different glucose/glutamine conditions, congruent with glycolytic activity, but not with LDH activity or the Warburg effect; this suggests metabolic compartmentation. Remarkably, kpl-values were almost two-fold higher in MCF-7 than in the more malignant MDA-MB-231 cells, the latter showing a higher flux of 13C-glucose-derived pyruvate to the TCA-cycle metabolites 13C2-citrate and 13C3-malate, i.e., pyruvate decarboxylation and carboxylation, respectively. Thus, MRS with hyperpolarized [1-13C-pyruvate] is sensitive to both the metabolic program and the nutritional state of cancer cells.
    Keywords:  13C-glucose metabolomics; LDH; TCA-cycle; Warburg effect; breast cancer cells; compartmentation; glycolysis; hyperpolarized 13C-pyruvate; nutrient deprivation; pyruvate kinase
    DOI:  https://doi.org/10.3390/cancers14071845
  6. Med (N Y). 2022 Feb 11. 3(2): 119-136
    Ketogenic diet and chemotherapy combine to disrupt pancreatic cancer metabolism and growth.
    Lifeng Yang, Tara TeSlaa, Serina Ng, Michel Nofal, Lin Wang, Taijin Lan, Xianfeng Zeng, Alexis Cowan, Matthew McBride, Wenyun Lu, Shawn Davidson, Gaoyang Liang, Tae Gyu Oh, Michael Downes, Ronald Evans, Daniel Von Hoff, Jessie Yanxiang Guo, Haiyong Han, Joshua D Rabinowitz.
       Background: Ketogenic diet is a potential means of augmenting cancer therapy. Here, we explore ketone body metabolism and its interplay with chemotherapy in pancreatic cancer.
    Methods: Metabolism and therapeutic responses of murine pancreatic cancer were studied using KPC primary tumors and tumor chunk allografts. Mice on standard high-carbohydrate diet or ketogenic diet were treated with cytotoxic chemotherapy (nab-paclitaxel, gemcitabine, cisplatin). Metabolic activity was monitored with metabolomics and isotope tracing, including 2H- and 13C-tracers, liquid chromatography-mass spectrometry, and imaging mass spectrometry.
    Findings: Ketone bodies are unidirectionally oxidized to make NADH. This stands in contrast to the carbohydrate-derived carboxylic acids lactate and pyruvate, which rapidly interconvert, buffering NADH/NAD. In murine pancreatic tumors, ketogenic diet decreases glucose's concentration and tricarboxylic acid cycle contribution, enhances 3-hydroxybutyrate's concentration and tricarboxylic acid contribution, and modestly elevates NADH, but does not impact tumor growth. In contrast, the combination of ketogenic diet and cytotoxic chemotherapy substantially raises tumor NADH and synergistically suppresses tumor growth, tripling the survival benefits of chemotherapy alone. Chemotherapy and ketogenic diet also synergize in immune-deficient mice, although long-term growth suppression was only observed in mice with an intact immune system.
    Conclusions: Ketogenic diet sensitizes murine pancreatic cancer tumors to cytotoxic chemotherapy. Based on these data, we have initiated a randomized clinical trial of chemotherapy with standard versus ketogenic diet for patients with metastatic pancreatic cancer (NCT04631445).
    DOI:  https://doi.org/10.1016/j.medj.2021.12.008
  7. Cancer Res. 2022 Apr 12. pii: canres.3230.2021. [Epub ahead of print]
    Mitochondrial calcium uniporter drives metastasis and confers a targetable cystine dependency in pancreatic cancer.
    Xiuchao Wang, Yunzhan Li, Zekun Li, Shengchen Lin, Hongwei Wang, Jianwei Sun, Chungen Lan, Liangliang Wu, Dongxiao Sun, Chongbiao Huang, Pankaj K Singh, Nadine Hempel, Mohamed Trebak, Gina M DeNicola, Jihui Hao, Shengyu Yang.
      Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease with few effective treatments. Here we show that the mitochondrial calcium uniporter (MCU) promotes PDAC cell migration, invasion, metastasis, and metabolic stress resistance by activating the Keap1-Nrf2 antioxidant program. The cystine transporter SLC7A11 was identified as a druggable target downstream of the MCU-Nrf2 axis. Paradoxically, despite the increased ability to uptake cystine, MCU-overexpressing PDAC demonstrated characteristics typical of cystine-deprived cells and were hypersensitive to cystine deprivation-induced ferroptosis. Pharmacological inhibitors of SLC7A11 effectively induced tumor regression and abrogated MCU-driven metastasis in PDAC. In patient-derived organoid models in vitro and patient-derived xenograft models in vivo, MCU-high PDAC demonstrated increased sensitivity to SLC7A11 inhibition compared to MCU-low tumors. These data suggest that MCU is able to promote resistance to metabolic stress and drive PDAC metastasis in a cystine-dependent manner. MCU-mediated cystine addiction could be exploited as a therapeutic vulnerability to inhibit PDAC tumor growth and prevent metastasis.
    DOI:  https://doi.org/10.1158/0008-5472.CAN-21-3230
  8. Biochem Pharmacol. 2022 Apr 12. pii: S0006-2952(22)00131-9. [Epub ahead of print] 115037
    A Rational Foundation for Micheliolide-based Combination Strategy by Targeting Redox and Metabolic Circuit in Cancer Cells.
    Jianshuang Guo, Kaihui Liu, Jiyan Wang, Hao Jiang, Mengyi Zhang, Yang Liu, Changliang Shan, Fangzhong Hu, Wenzheng Fu, Chunze Zhang, Jing Li, Yue Chen.
      Accumulating evidence has supported that targeting oxidative stress and metabolic alterations of cancer is an effective strategy to combat cancer. We previously reported that Dimethylaminomicheliolide (DMAMCL) and its active metabolite micheliolide (MCL) can cause oxidative stress and cell death in leukemia and glioblastoma. However, the detailed mechanism underlying MCL or DMAMCL triggered oxidative stress remains elusive. Herein, using leukemia HL60 cells and glioblastoma U118MG cells as models, we found that MCL-induced oxidative stress is mainly mediated by reduced glutathione (GSH). Overproduced reactive oxygen species (ROS) can lead to oxidative damage to mitochondrial, impairing the ability of the tricarboxylic acid (TCA) cycle and causing dysfunction of mitochondrial respiratory chain. On the other hand, the depletion of GSH activates GSH biosynthesis pathway and has possibility to give rise to more GSH to scavenge ROS in cancer cells. Targeting this redox and metabolic circuit, we identified L-buthionine sulfoximine (BSO), an inhibitor in GSH biosynthesis, as an agent that can enhance MCL regimen to inhibit GSH compensatory event and thereby further facilitate cancer cell oxidative stress. Together, these results illustrate that targeting redox and metabolic pathway by MCL/DMAMCL combination with BSO is a potent therapeutic intervention for the treatments of glioblastoma and acute-myelocytic leukemia.
    Keywords:  glioblastoma; glutathione metabolism; leukemia; micheliolide; mitochondrial dysfunction; oxidative stress
    DOI:  https://doi.org/10.1016/j.bcp.2022.115037
  9. Cancers (Basel). 2022 Mar 31. pii: 1776. [Epub ahead of print]14(7):
    Estrogens and Progestins Cooperatively Shift Breast Cancer Cell Metabolism.
    Ashley V Ward, Shawna B Matthews, Lynsey M Fettig, Duncan Riley, Jessica Finlay-Schultz, Kiran V Paul, Matthew Jackman, Peter Kabos, Paul S MacLean, Carol A Sartorius.
      Metabolic reprogramming remains largely understudied in relation to hormones in estrogen receptor (ER) and progesterone receptor (PR) positive breast cancer. In this study, we investigated how estrogens, progestins, or the combination, impact metabolism in three ER and PR positive breast cancer cell lines. We measured metabolites in the treated cells using ultra-performance liquid chromatography coupled with mass spectrometry (UPLC-MS). Top metabolic processes upregulated with each treatment involved glucose metabolism, including Warburg effect/glycolysis, gluconeogenesis, and the pentose phosphate pathway. RNA-sequencing and pathway analysis on two of the cell lines treated with the same hormones, found estrogens target oncogenes, such as MYC and PI3K/AKT/mTOR that control tumor metabolism, while progestins increased genes associated with fatty acid metabolism, and the estrogen/progestin combination additionally increased glycolysis. Phenotypic analysis of cell energy metabolism found that glycolysis was the primary hormonal target, particularly for the progestin and estrogen-progestin combination. Transmission electron microscopy found that, compared to vehicle, estrogens elongated mitochondria, which was reversed by co-treatment with progestins. Progestins promoted lipid storage both alone and in combination with estrogen. These findings highlight the shift in breast cancer cell metabolism to a more glycolytic and lipogenic phenotype in response to combination hormone treatment, which may contribute to a more metabolically adaptive state for cell survival.
    Keywords:  breast cancer; estrogen receptor; estrogens; glycolysis; metabolism; progesterone receptor; progestins
    DOI:  https://doi.org/10.3390/cancers14071776
  10. J Fluoresc. 2022 Apr 14.
    Development of Optical Biosensor for the Detection of Glutamine in Human Biofluids Using Merocyanine Dye.
    Vijayakumar Sathya, Appadurai Deepa, Lakshmi Kandhan Sangeetha, Venkatesan Srinivasadesikan, Shyi-Long Lee, Vediappen Padmini.
      Merocyanine dye based fluorescent organic compound has been synthesized for the detection of glutamine. The probe showed remarkable fluorescent intensity with glutamine through ICT (Intermolecular Charge Transfer Mechanism). Hence, it is tested for the detection of glutamine using colorimetric and fluorimetric techniques in physiological and neutral pH (7.2). Under optimized experimental conditions, the probe detects glutamine selectively among other interfering biomolecules. The probe has showed a LOD (lower limit of detection) of 9.6 × 10-8 mol/L at the linear range 0-180 µM towards glutamine. The practical application of the probe is successfully tested in human biofluids.
    Keywords:  Competitive study; Fluorimetry biosensor; Glutamine; LOD
    DOI:  https://doi.org/10.1007/s10895-022-02937-y
  11. J Hazard Mater. 2022 Apr 01. pii: S0304-3894(22)00609-4. [Epub ahead of print]434 128820
    Integrative proteomics and metabolomics approach to elucidate metabolic dysfunction induced by silica nanoparticles in hepatocytes.
    Ye Zhu, Yukang Zhang, Yanbo Li, Caixia Guo, Zhuying Fan, Yang Li, Man Yang, Xianqing Zhou, Zhiwei Sun, Ji Wang.
      Silica nanoparticles (SiNPs) are derived from manufactured materials and the natural environment, and they cause detrimental effects on human health via various exposure routes. The liver is proven to be a key target organ for SiNP toxicity; however, the mechanisms causing toxicity remain largely uncertain. Here, we investigated the effects of SiNPs on the metabolic spectrum in hepatocytes via integrative analyses of proteomics and metabolomics. First, a proteomic analysis was used to screen for critical proteins (including RPL3, HSP90AA1, SOD, PGK1, GOT1, and PNP), indicating that abnormal protein synthesis, protein misfolding, oxidative stress, and metabolic dysfunction may contribute to SiNP-induced hepatotoxicity. Next, metabolomic data demonstrated that SiNPs caused metabolic dysfunction by altering vital metabolites (including glucose, alanine, GSH, CTP, and ATP). Finally, a systematic bioinformatic analysis of protein-metabolite interactions showed that SiNPs disturbed glucose metabolism (glycolysis and pentose phosphate pathways, amino acid metabolism (alanine, aspartate, and glutamate), and ribonucleotide metabolism (purine and pyrimidine). These metabolic dysfunctions could exacerbate oxidative stress and lead to liver injury. Moreover, SOD, TKT, PGM1, GOT1, PNP, and NME2 may be key proteins for SiNP-induced hepatotoxicity. This study revealed the metabolic mechanisms underlying SiNP-induced hepatotoxicity and illustrated that integrative omics analyses can be a powerful approach for toxicity evaluations and risk assessments of nanoparticles.
    Keywords:  Hepatotoxicity; Metabolomics; Proteomics; Silica nanoparticles
    DOI:  https://doi.org/10.1016/j.jhazmat.2022.128820
  12. Int J Mol Sci. 2022 Mar 29. pii: 3745. [Epub ahead of print]23(7):
    Pyruvate Dehydrogenase Kinase Inhibition by Dichloroacetate in Melanoma Cells Unveils Metabolic Vulnerabilities.
    Jiske F Tiersma, Bernard Evers, Barbara M Bakker, Mathilde Jalving, Steven de Jong.
      Melanoma is characterized by high glucose uptake, partially mediated through elevated pyruvate dehydrogenase kinase (PDK), making PDK a potential treatment target in melanoma. We aimed to reduce glucose uptake in melanoma cell lines through PDK inhibitors dichloroacetate (DCA) and AZD7545 and through PDK knockdown, to inhibit cell growth and potentially unveil metabolic co-vulnerabilities resulting from PDK inhibition. MeWo cells were most sensitive to DCA, while SK-MEL-2 was the least sensitive, with IC50 values ranging from 13.3 to 27.0 mM. DCA strongly reduced PDH phosphorylation and increased the oxygen consumption rate:extracellular acidification rate (OCR:ECAR) ratio up to 6-fold. Knockdown of single PDK isoforms had similar effects on PDH phosphorylation and OCR:ECAR ratio as DCA but did not influence sensitivity to DCA. Growth inhibition by DCA was synergistic with the glutaminase inhibitor CB-839 (2- to 5-fold sensitization) and with diclofenac, known to inhibit monocarboxylate transporters (MCTs) (3- to 8-fold sensitization). CB-839 did not affect the OCR:ECAR response to DCA, whereas diclofenac strongly inhibited ECAR and further increased the OCR:ECAR ratio. We conclude that in melanoma cell lines, DCA reduces proliferation through reprogramming of cellular metabolism and synergizes with other metabolically targeted drugs.
    Keywords:  dichloroacetate; melanoma; metabolic reprogramming; metabolism
    DOI:  https://doi.org/10.3390/ijms23073745
  13. Cell Rep. 2022 Apr 12. pii: S2211-1247(22)00412-0. [Epub ahead of print]39(2): 110660
    SENP1-Sirt3 signaling promotes α-ketoglutarate production during M2 macrophage polarization.
    Wei Zhou, Gaolei Hu, Jianli He, Tianshi Wang, Yong Zuo, Ying Cao, Quan Zheng, Jun Tu, Jiao Ma, Rong Cai, Yalan Chen, Qiuju Fan, Baijun Dong, Hongsheng Tan, Qi Wang, Wei Xue, Jinke Cheng.
      The metabolic program is altered during macrophage activation and influences macrophage polarization. Glutaminolysis promotes accumulation of α-ketoglutarate (αKG), leading to Jumonji domain-containing protein D3 (Jmjd3)-dependent demethylation at H3K27me3 during M2 polarization of macrophages. However, it remains unclear how αKG accumulation is regulated during M2 polarization of macrophages. This study shows that SENP1-Sirt3 signaling controls glutaminolysis, leading to αKG accumulation during IL-4-stimulated M2 polarization. Activation of the SENP1-Sirt3 axis augments M2 macrophage polarization through the accumulation of αKG via glutaminolysis. We also identify glutamate dehydrogenase 1 (GLUD1) as an acetylated protein in mitochondria. The SENP1-Sirt3 axis deacetylates GLUD1 and increases its activity in glutaminolysis to promote αKG production, leading to M2 polarization of macrophages. Therefore, SENP1-Sirt3 signaling plays a critical role in αKG accumulation via glutaminolysis to promote M2 polarization.
    Keywords:  CP: Immunology; SENP1; SUMOylation; Sirt3; macrophage M2 polarization; α-ketoglutarate
    DOI:  https://doi.org/10.1016/j.celrep.2022.110660
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