bims-glucam Biomed News
on Glutamine cancer metabolism
Issue of 2022–09–18
sixteen papers selected by
Sreeparna Banerjee, Middle East Technical University
  1. A happy cell stays home: When metabolic stress creates epigenetic advantages in the tumor microenvironment.
  2. Inhibition of glutaminolysis ameliorates lupus by regulating T and B cell subsets and downregulating the mTOR/P70S6K/4EBP1 and NLRP3/caspase-1/IL-1β pathways in MRL/lpr mice.
  3. Sex differences in brain tumor glutamine metabolism reveal sex-specific vulnerabilities to treatment.
  4. Metabolic reprogramming: A novel metabolic model for pulmonary hypertension.
  5. Energy metabolism pathways in breast cancer progression: The reprogramming, crosstalk, and potential therapeutic targets.
  6. Metabolic reprogramming in the OPA1-deficient cells.
  7. Subtype and site specific-induced metabolic vulnerabilities in prostate cancer.
  8. Folate enzyme MTHFD2 links one-carbon metabolism to unfolded protein response in glioblastoma.
  9. Gain-of-function genetic screens in human cells identify SLC transporters overcoming environmental nutrient restrictions.
  10. Evaluation of Glutaminolysis in T Cells.
  11. Recent advances of IDH1 mutant inhibitor in cancer therapy.
  12. Gankyrin and TIGAR cooperatively accelerate glucose metabolism toward PPP and TCA cycle in hepatocellular carcinoma.
  13. An integrative cellular metabolomic study reveals downregulated tricarboxylic acid cycle and potential biomarkers induced by tetrabromobisphenol A in human lung A549 cells.
  14. Colorectal cancer: Metabolic interactions reshape the tumor microenvironment.
  15. Control of cell metabolism by the epidermal growth factor receptor.
  16. Drosophila as a toolkit to tackle cancer and its metabolism.
  1. Front Oncol. 2022 ;12 962928
    A happy cell stays home: When metabolic stress creates epigenetic advantages in the tumor microenvironment.
    Eric A Hanse, Mei Kong.
      A paradox of fast-proliferating tumor cells is that they deplete extracellular nutrients that often results in a nutrient poor microenvironment in vivo. Having a better understanding of the adaptation mechanisms cells exhibit in response to metabolic stress will open new therapeutic windows targeting the tumor's extreme nutrient microenvironment. Glutamine is one of the most depleted amino acids in the tumor core and here, we provide insight into how important glutamine and its downstream by-product, α-ketoglutarate (αKG), are to communicating information about the nutrient environment. This communication is key in the cell's ability to foster adaptation. We highlight the epigenetic changes brought on when αKG concentrations are altered in cancer and discuss how depriving cells of glutamine may lead to cancer cell de-differentiation and the ability to grow and thrive in foreign environments. When we starve cells, they adapt to survive. Those survival "skills" allow them to go out looking for other places to live and metastasize. We further examine current challenges to modelling the metabolic tumor microenvironment in the laboratory and discuss strategies that consider current findings to target the tumor's poor nutrient microenvironment.
    Keywords:  alpha ketoglutarate; epigenetics; glutamine; glutaminolysis-inhibition; metabolism; tumor; tumor microenvironment
    DOI:  https://doi.org/10.3389/fonc.2022.962928
  2. Int Immunopharmacol. 2022 Sep 13. pii: S1567-5769(22)00617-8. [Epub ahead of print]112 109133
    Inhibition of glutaminolysis ameliorates lupus by regulating T and B cell subsets and downregulating the mTOR/P70S6K/4EBP1 and NLRP3/caspase-1/IL-1β pathways in MRL/lpr mice.
    Xiaomei Zhang, Gang Wang, Ying Bi, Zhihang Jiang, Xiaofei Wang.
       BACKGROUND AND AIM OF THE STUDY: Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by lymphocyte imbalance. The differentiation and function of T and B cells receive regulation from intracellular energy metabolism. Herein, we aimed to investigate glutamine metabolism levels in SLE and explore the effects of modulating glutamine metabolism on T and B cell subsets and related signaling pathways in MRL/lpr lupus mice.
    METHODS: We assessed intracellular glutamine metabolism in SLE patients and MRL/lpr mice by measuring intracellular glutamate and Glutaminase 1 (GLS1) protein levels. Intraperitoneal injection of the GLS1 inhibitor CB839 was performed to reduce glutamine metabolism and lupus-like manifestations in MRL/lpr mice were evaluated. The proportions and numbers of T and B cell subsets were determinedvia flow cytometry. Pathway-related proteins were detected using western blotting.
    RESULTS: In this study, we reported that glutamine metabolism levels were aberrantly elevated in splenic mononuclear cells from MRL/lpr lupus mice, as well as in peripheral blood mononuclear cells (PBMCs) of SLE patients. Inhibition of glutamine metabolism by CB839 treatment for 8 weeks alleviated the lupus-like manifestations in MRL/lpr mice, including the kidney lesions, urinary protein/creatinine ratio, spleen index, and serum IgG1. Meanwhile, CB839 treatment ameliorated the depletion of IL-10 producing B cells (B10) and adjusted the Th1/TH2 and TH17/Treg imbalance. The inhibition of GLS1 by CB839 reduced the numbers of follicular helper T (TfH) cells and activated B cells in lupus mice. The proportions of mature B cells and plasma cells were not affected. Furthermore, the hyperactivated mTOR/P70S6K/4EBP1 and NLRP3/caspase-1/IL-1β pathways in MRL/lpr mice were reversed by CB839 treatment.
    CONCLUSION: Our study confirmed the presence of abnormal intracellular glutamine metabolism in SLE and revealed potential therapeutic targets for this disease.
    Keywords:  B cell subsets; CB839; Glutamine metabolism; Lupus nephritis; NLRP3 pathway; Systemic lupus erythematosus; T cell subsets; mTOR pathway
    DOI:  https://doi.org/10.1016/j.intimp.2022.109133
  3. Med (N Y). 2022 Sep 08. pii: S2666-6340(22)00365-8. [Epub ahead of print]
    Sex differences in brain tumor glutamine metabolism reveal sex-specific vulnerabilities to treatment.
    Jasmin Sponagel, Jill K Jones, Cheryl Frankfater, Shanshan Zhang, Olivia Tung, Kevin Cho, Kelsey L Tinkum, Hannah Gass, Elena Nunez, Douglas R Spitz, Prakash Chinnaiyan, Jacob Schaefer, Gary J Patti, Maya S Graham, Audrey Mauguen, Milan Grkovski, Mark P Dunphy, Simone Krebs, Jingqin Luo, Joshua B Rubin, Joseph E Ippolito.
       BACKGROUND: Brain cancer incidence and mortality rates are greater in males. Understanding the molecular mechanisms that underlie those sex differences could improve treatment strategies. Although sex differences in normal metabolism are well described, it is currently unknown whether they persist in cancerous tissue.
    METHODS: Using positron emission tomography (PET) imaging and mass spectrometry, we assessed sex differences in glioma metabolism in samples from affected individuals. We assessed the role of glutamine metabolism in male and female murine transformed astrocytes using isotope labeling, metabolic rescue experiments, and pharmacological and genetic perturbations to modulate pathway activity.
    FINDINGS: We found that male glioblastoma surgical specimens are enriched for amino acid metabolites, including glutamine. Fluoroglutamine PET imaging analyses showed that gliomas in affected male individuals exhibit significantly higher glutamine uptake. These sex differences were well modeled in murine transformed astrocytes, in which male cells imported and metabolized more glutamine and were more sensitive to glutaminase 1 (GLS1) inhibition. The sensitivity to GLS1 inhibition in males was driven by their dependence on glutamine-derived glutamate for α-ketoglutarate synthesis and tricarboxylic acid (TCA) cycle replenishment. Females were resistant to GLS1 inhibition through greater pyruvate carboxylase (PC)-mediated TCA cycle replenishment, and knockdown of PC sensitized females to GLS1 inhibition.
    CONCLUSION: Our results show that clinically important sex differences exist in targetable elements of metabolism. Recognition of sex-biased metabolism may improve treatments through further laboratory and clinical research.
    FUNDING: This work was supported by NIH grants, Joshua's Great Things, the Siteman Investment Program, and the Barnard Research Fund.
    Keywords:  TCA cycle; Translation to patients; cancer metabolism; glioma; glutaminase; glutamine metabolism; glutathione; pyruvate carboxylase; sex differences; solid-state NMR; α-ketoglutarate
    DOI:  https://doi.org/10.1016/j.medj.2022.08.005
  4. Front Cardiovasc Med. 2022 ;9 957524
    Metabolic reprogramming: A novel metabolic model for pulmonary hypertension.
    Xuhan Liu, Liping Zhang, Weihua Zhang.
      Pulmonary arterial hypertension, or PAH, is a condition that is characterized by pulmonary artery pressures above 20 mmHg (at rest). In the treatment of PAH, the pulmonary vascular system is regulated to ensure a diastolic and contraction balance; nevertheless, this treatment does not prevent or reverse pulmonary vascular remodeling and still causes pulmonary hypertension to progress. According to Warburg, the link between metabolism and proliferation in PAH is similar to that of cancer, with a common aerobic glycolytic phenotype. By activating HIF, aerobic glycolysis is enhanced and cell proliferation is triggered. Aside from glutamine metabolism, the Randle cycle is also present in PAH. Enhanced glutamine metabolism replenishes carbon intermediates used by glycolysis and provides energy to over-proliferating and anti-apoptotic pulmonary vascular cells. By activating the Randle cycle, aerobic oxidation is enhanced, ATP is increased, and myocardial injury is reduced. PAH is predisposed by epigenetic dysregulation of DNA methylation, histone acetylation, and microRNA. This article discusses the abnormal metabolism of PAH and how metabolic therapy can be used to combat remodeling.
    Keywords:  FAO; PAH; glutamine; metabolism; mitochondria; randle cycle
    DOI:  https://doi.org/10.3389/fcvm.2022.957524
  5. Transl Oncol. 2022 Sep 13. pii: S1936-5233(22)00193-0. [Epub ahead of print]26 101534
    Energy metabolism pathways in breast cancer progression: The reprogramming, crosstalk, and potential therapeutic targets.
    Xuewei Zheng, Haodi Ma, Jingjing Wang, Mengjiao Huang, Dongliao Fu, Ling Qin, Qinan Yin.
      Breast cancer (BC) is a malignant tumor that seriously endangers health in women. BC, like other cancers, is accompanied by metabolic reprogramming. Among energy metabolism-related pathways, BC exhibits enhanced glycolysis, tricarboxylic acid (TCA) cycle, pentose phosphate pathway (PPP), glutamate metabolism, and fatty acid metabolism activities. These pathways facilitate the proliferation, growth and migration of BC cells. The progression of BC is closely related to the alterations in the activity or expression level of several metabolic enzymes, which are regulated by the intrinsic factors such as the key signaling and transcription factors. The metabolic reprogramming in the progression of BC is attributed to the aberrant expression of the signaling and transcription factors associated with the energy metabolism pathways. Understanding the metabolic mechanisms underlying the development of BC will provide a druggable potential for BC treatment and drug discovery.
    Keywords:  Breast cancer (BC); Glutamine metabolism; Glycolysis; Metabolic reprogramming; Transcription factors
    DOI:  https://doi.org/10.1016/j.tranon.2022.101534
  6. Cell Mol Life Sci. 2022 Sep 14. 79(10): 517
    Metabolic reprogramming in the OPA1-deficient cells.
    Wenting Dai, Zhichao Wang, Qiong A Wang, David Chan, Lei Jiang.
      OPA1, a dynamin-related GTPase mutated in autosomal dominant optic atrophy, is essential for the fusion of the inner mitochondrial membrane. Although OPA1 deficiency leads to impaired mitochondrial morphology, the role of OPA1 in central carbon metabolism remains unclear. Here, we aim to explore the functional role and metabolic mechanism of OPA1 in cell fitness beyond the control of mitochondrial fusion. We applied [U-13C]glucose and [U-13C]glutamine isotope tracing techniques to OPA1-knockout (OPA1-KO) mouse embryonic fibroblasts (MEFs) compared to OPA1 wild-type (OPA1-WT) controls. Furthermore, the resulting tracing data were integrated by metabolic flux analysis to understand the underlying metabolic mechanism through which OPA1 deficiency reprograms cellular metabolism. OPA1-deficient MEFs were depleted of intracellular citrate, which was consistent with the decreased oxygen consumption rate in these cells with mitochondrial fission that is not balanced by mitochondrial fusion. Whereas oxidative glucose metabolism was impaired, OPA1-deficient cells activated glutamine-dependent reductive carboxylation and subsequently relied on this reductive metabolism to produce cytosolic citrate as a predominant acetyl-CoA source for de novo fatty acid synthesis. Prevention of cytosolic glutamine reductive carboxylation by GSK321, an inhibitor of isocitrate dehydrogenase 1 (IDH1), largely repressed lipid synthesis and blocked cell proliferation in OPA1-deficient MEFs. Our data support that, when glucose oxidation failed to support lipogenesis and proliferation in cells with unbalanced mitochondrial fission, OPA1 deficiency stimulated metabolic anaplerosis into glutamine-dependent reductive carboxylation in an IDH1-mediated manner.
    Keywords:  Cell growth; Citrate; De novo lipogenesis; OPA1 dysfunction; Oxidative metabolism; Reductive carboxylation
    DOI:  https://doi.org/10.1007/s00018-022-04542-5
  7. Mol Cancer Res. 2022 Sep 16. pii: MCR-22-0250. [Epub ahead of print]
    Subtype and site specific-induced metabolic vulnerabilities in prostate cancer.
    Federica Mossa, Daniele Robesti, Ramachandran Sumankalai, Eva Corey, Mark Titus, Yuqi Kang, Jianhua Zhang, Alberto Briganti, Francesco Montorsi, Christopher P Vellano, Joseph R Marszalek, Daniel E Frigo, Christopher J Logothetis, Taranjit S Gujral, Eleonora Dondossola.
      Aberrant metabolic functions play a crucial role in prostate cancer progression and lethality. Currently, limited knowledge is available on subtype-specific metabolic features and their implications for treatment. We therefore investigated the metabolic determinants of the two major subtypes of castration-resistant prostate cancer (androgen receptor-expressing prostate cancer, ARPC; and aggressive-variant prostate cancer, AVPC). Transcriptomic analyses revealed enrichment of gene sets involved in oxidative phosphorylation (OXPHOS) in ARPC tumor samples compared to AVPC. Unbiased screening of metabolic signaling pathways in PDX models by proteomic analyses further supported an enrichment of OXPHOS in ARPC compared to AVPC, and a skewing toward glycolysis by AVPC. In vitro, ARPC C4-2B cells depended on aerobic respiration, while AVPC PC3 cells relied more heavily on glycolysis, as further confirmed by pharmacological interference using IACS-10759, a clinical-grade inhibitor of OXPHOS. In vivo studies confirmed IACS-10759's inhibitory effects in subcutaneous and bone-localized C4-2B tumors, and no effect in subcutaneous PC3 tumors. Unexpectedly, IACS-10759 inhibited PC3 tumor growth in bone, indicating microenvironment-induced metabolic reprogramming. These results suggest that castration-resistant ARPC and AVPC exhibit different metabolic dependencies, which can further undergo metabolic reprogramming in bone. Implications: These vulnerabilities may be exploited with mechanistically novel treatments, such as those targeting OXPHOS alone or possibly in combination with existing therapies. In addition, our findings underscore the impact of the tumor microenvironment in reprogramming prostate cancer metabolism.
    DOI:  https://doi.org/10.1158/1541-7786.MCR-22-0250
  8. Cancer Lett. 2022 Sep 08. pii: S0304-3835(22)00387-1. [Epub ahead of print] 215903
    Folate enzyme MTHFD2 links one-carbon metabolism to unfolded protein response in glioblastoma.
    Zhiyuan Zhu, Karrie Mei-Yee Kiang, Ning Li, Jiaxin Liu, Pingde Zhang, Lei Jin, Xiaozheng He, Shizhong Zhang, Gilberto Ka-Kit Leung.
      The mitochondrial folate enzyme methylenetetrahydrofolate dehydrogenase/cyclohydrolase (MTHFD2) has shown oncogenic roles in various cancers and may have non-metabolic functions. This study investigated the role of MTHFD2 in glioblastoma pathogenesis. We find that MTHFD2 expression is enriched in gliomas by analysing public databases and clinical specimens. RNA interference (RNAi) and inhibitor of MTHFD2 hamper the proliferation of glioblastoma and induce apoptosis in cell lines, glioma stem-like cells (GSCs) and patient-derived xenografts (PDX). Metabolomic analyses show that MTHFD2 depletion suppresses the central carbon metabolic pathways, including glycolysis, the pentose phosphate pathway (PPP), and the tricarboxylic acid (TCA) cycle. GSEA reveals a novel non-metabolic function of MTHFD2 in association with the unfolded protein response (UPR). MTHFD2 depletion activates the PERK/eIF2α axis which contributes to translation inhibition and apoptosis; these effects are attenuated by a PERK inhibitor. Mechanistically, MTHFD2 may be linked to UPR via the post-transcriptionally regulation of chaperone protein GRP78. In conclusion, MTHFD2 could be a promising therapeutic target for glioblastoma. Besides its canonical role, MTHFD2 may contribute to glioblastoma pathogenesis via UPR, highlighting a newly identified functional link between one-carbon metabolism and cell stress response.
    Keywords:  ER stress; Metabolic reprogramming; Metabolomics; Non-metabolic; RNA interference
    DOI:  https://doi.org/10.1016/j.canlet.2022.215903
  9. Life Sci Alliance. 2022 Nov;pii: e202201404. [Epub ahead of print]5(11):
    Gain-of-function genetic screens in human cells identify SLC transporters overcoming environmental nutrient restrictions.
    Manuele Rebsamen, Enrico Girardi, Vitaly Sedlyarov, Stefania Scorzoni, Konstantinos Papakostas, Manuela Vollert, Justyna Konecka, Bettina Guertl, Kristaps Klavins, Tabea Wiedmer, Giulio Superti-Furga.
      Solute carrier (SLC) transporters control fluxes of nutrients and metabolites across membranes and thereby represent a critical interface between the microenvironment and cellular and subcellular metabolism. Because of substantial functional overlap, the interplay and relative contributions of SLCs in response to environmental stresses remain poorly elucidated. To infer functional relationships between SLCs and metabolites, we developed a strategy to identify SLCs able to sustain cell viability and proliferation under growth-limiting concentrations of essential nutrients. One-by-one depletion of 13 amino acids required for cell proliferation enabled gain-of-function genetic screens using a SLC-focused CRISPR/Cas9-based transcriptional activation approach to uncover transporters relieving cells from growth-limiting metabolic bottlenecks. Among the transporters identified, we characterized the cationic amino acid transporter SLC7A3 as a gene that, when up-regulated, overcame low availability of arginine and lysine by increasing their uptake, whereas SLC7A5 was able to sustain cellular fitness upon deprivation of several neutral amino acids. Moreover, we identified metabolic compensation mediated by the glutamate/aspartate transporters SLC1A2 and SLC1A3 under glutamine-limiting conditions. Overall, this gain-of-function approach using human cells uncovered functional transporter-nutrient relationships and revealed that transport activity up-regulation may be sufficient to overcome environmental metabolic restrictions.
    DOI:  https://doi.org/10.26508/lsa.202201404
  10. Curr Protoc. 2022 Sep;2(9): e540
    Evaluation of Glutaminolysis in T Cells.
    Masaki Tajima, Warren Strober.
      The activity of living cells is necessarily dependent on the amount of available bioenergy. In T cells, the latter is mainly derived from ATP, a molecular energy "coin" generated by one of several metabolic processes that differ in their ability to satisfy energy demand. Thus, whereas naïve or quiescent T cells efficiently utilize oxidative phosphorylation to generate ATP, T cells subjected to antigenic stimulation followed by clonal expansion and cytokine production meet their increased need for energy by supplementing ATP generation by oxidative phosphorylation with ATP generation by glycolysis. Yet additional need for ATP can be met by other basic biologic sources of energy such as glutamine, an amino acid that is metabolized through a process called glutaminolysis to result in end products that flows into the TCA cycle and augment ATP generation by oxidative phosphorylation. It is now possible to track the dominant energy supplying processes (i.e., the ATP generation process) in differentiating or activated T cells in a real-time manner. Here, we provide one element of such tracking by describing protocols for the assessment of the contribution of glutaminolysis to overall ATP production within different T cell subsets. © 2022 Wiley Periodicals LLC. This article has been contributed to by US Government employees and their work is in the public domain in the USA. Basic Protocol 1: Evaluation of the role of glutaminolysis during T cell activation/differentiation Basic Protocol 2: Evaluation of the role of glutaminolysis in T cell responses utilizing glutaminolysis inhibitors Basic Protocol 3: Evaluation of the effect of glutaminolysis on cellular oxidative phosphorylation/glycolysis.
    Keywords:  T cell; glutaminolysis; glycolysis; oxidative phosphorylation
    DOI:  https://doi.org/10.1002/cpz1.540
  11. Front Pharmacol. 2022 ;13 982424
    Recent advances of IDH1 mutant inhibitor in cancer therapy.
    Wangqi Tian, Weitong Zhang, Yifan Wang, Ruyi Jin, Yuwei Wang, Hui Guo, Yuping Tang, Xiaojun Yao.
      Isocitrate dehydrogenase (IDH) is the key metabolic enzyme that catalyzes the conversion of isocitrate to α-ketoglutarate (α-KG). Two main types of IDH1 and IDH2 are present in humans. In recent years, mutations in IDH have been observed in several tumors, including glioma, acute myeloid leukemia, and chondrosarcoma. Among them, the frequency of IDH1 mutations is higher than IDH2. IDH1 mutations have been shown to increase the conversion of α-KG to 2-hydroxyglutarate (2-HG). IDH1 mutation-mediated accumulation of 2-HG leads to epigenetic dysregulation, altering gene expression, and impairing cell differentiation. A rapidly emerging therapeutic approach is through the development of small molecule inhibitors targeting mutant IDH1 (mIDH1), as evidenced by the recently approved of the first selective IDH1 mutant inhibitor AG-120 (ivosidenib) for the treatment of IDH1-mutated AML. This review will focus on mIDH1 as a therapeutic target and provide an update on IDH1 mutant inhibitors in development and clinical trials.
    Keywords:  2-HG; hypermethylation; isocitrate dehydrogenase mutation; mIDH1 inhibitors; natural product
    DOI:  https://doi.org/10.3389/fphar.2022.982424
  12. Cancer Sci. 2022 Sep 17.
    Gankyrin and TIGAR cooperatively accelerate glucose metabolism toward PPP and TCA cycle in hepatocellular carcinoma.
    Chun Yang, Xiao-Wen Cui, Zhi-Wen Ding, Tian-Yi Jiang, Xiao-Fan Feng, Yu-Fei Pan, Yun-Kai Lin, Tai-Yu Shang, Qing Wang, Jian Pan, Jian Wang, Hong-Yang Wang, Li-Wei Dong.
      Oncogene-derived metabolic reprogramming is important for anabolic growth of cancer cells, which is now considered not to be simply rely on glycolysis and passively caused by mitochondrial damage. The present work focused on gankyrin, a relatively specific oncogene in hepatocellular carcinoma (HCC), and its impact on glycolysis and mitochondrial homeostasis. Metabolomics, RNA-seq analysis and subsequent conjoint analysis illustrated that gankyrin regulated pentose phosphate pathway (PPP), tricarboxylic acid (TCA) cycle and mitochondrial function and homeostasis, which process pivotal roles in tumor development. Mechanistically, gankyrin was found to modulate HCC metabolic reprogramming via TIGAR. Gankyrin positively regulated the transcription of TIGAR through Nrf2, which bound to the antioxidant response elements (AREs) in the promoter of TIGAR. Interestingly, TIGAR feedback regulated the transcription of Nrf2 and subsequently gankyrin by promoting nuclear importation of PGC1α. The loop between gankyrin, Nrf2 and TIGAR accelerated glucose metabolism toward PPP and TCA cycle, which provided vital building blocks, such as NADPH, ATP and ribose of tumor and further facilitated progression of HCC.
    Keywords:  Gankyrin; TIGAR; metabolism reprogram; mitochondrial function; pentose phosphate pathway
    DOI:  https://doi.org/10.1111/cas.15593
  13. Environ Toxicol. 2022 Sep 15.
    An integrative cellular metabolomic study reveals downregulated tricarboxylic acid cycle and potential biomarkers induced by tetrabromobisphenol A in human lung A549 cells.
    Hailang He, Tingyu Pan, Xiaojian Shi, Shuang Yang, Paniz Jasbi, Yan Jin, Julia Yue Cui, Haiwei Gu.
      Tetrabromobisphenol A (TBBPA) is extensively utilized as a brominated flame retardant in numerous chemical products. As an environmental contaminant, the potential human toxicity of TBBPA has been attracting increasing attention. Nonetheless, the exact underlying mechanisms of toxicological effects caused by TBBPA remain uncertain. In this study, we investigated the potential mechanisms of TBBPA toxicity in vitro in the A549 cell line, one of the widely used type II pulmonary epithelial cell models in toxicology research. Cell viability was determined after treatment with varying concentrations of TBBPA. Liquid chromatography-mass spectrometry (LC-MS) metabolomics and metabolic flux approaches were utilized to evaluate metabolite and tricarboxylic acid (TCA) cycle oxidative flux changes. Our findings demonstrated that TBBPA significantly reduced the viability of cells and attenuated mitochondrial respiration in A549 cells. Additionally, LC-MS data showed significant reductions in TCA cycle metabolites including citrate, malate, fumarate, and alpha-ketoglutarate in 50 μM TBBPA-treated A549 cells. Metabolic flux analysis indicated reduced oxidative capacity in mitochondrial metabolism following TBBPA exposure. Moreover, diverse metabolic pathways, particularly alanine, aspartate, and glutamate metabolism and the TCA cycle, were found to be dysregulated. In total, 12 metabolites were significantly changed (p < .05) in response to 50 μM TBBPA exposure. Our results provide potential biomarkers of TBBPA toxicity in A549 cells and help elucidate the molecular mechanisms of pulmonary toxicity induced by TBBPA exposure.
    Keywords:  A549 cells; metabolic flux; metabolomics; pulmonary toxicity; tetrabromobisphenol A
    DOI:  https://doi.org/10.1002/tox.23657
  14. Biochim Biophys Acta Rev Cancer. 2022 Sep 10. pii: S0304-419X(22)00122-6. [Epub ahead of print] 188797
    Colorectal cancer: Metabolic interactions reshape the tumor microenvironment.
    Jiawei Chen, Haodong Zhu, Yuhang Yin, Siyuan Jia, Xiangjian Luo.
      Colorectal cancer (CRC) is one of the most common cancers worldwide, which ranks third in terms of incidence and the second leading cause of cancer-related mortality. Metabolic reprogramming within the tumor microenvironment (TME) has been proved intimately involved in the initiation and malignant progression of CRC. Signal messengers, including cytokines, metabolites, and exosomes among others, derived from cancer cells can be utilized by the surrounding cells within the TME to induce metabolic alteration and cancer-associated transformation. In turn, the cargos secreted from cancer-associate cells further provide the nutrition and energy supply for cancer cells, supporting their metabolic reprogramming to promote proliferation, migration, metastasis, and radiochemoresistance. In this review, we focus on the main cellular components in the TME: CAFs, TAMs, lymphocytes and neutrophils, and enumerate and integrate how the metabolic interactions between these components and cancer cells reshape TME to foster CRC malignancy.
    Keywords:  Colorectal cancer; Metabolic reprogramming; Tumor microenvironment
    DOI:  https://doi.org/10.1016/j.bbcan.2022.188797
  15. Biochim Biophys Acta Mol Cell Res. 2022 Sep 08. pii: S0167-4889(22)00151-3. [Epub ahead of print] 119359
    Control of cell metabolism by the epidermal growth factor receptor.
    Laura A Orofiamma, Dafne Vural, Costin N Antonescu.
      The epidermal growth factor receptor (EGFR) triggers the activation of many intracellular signals that control cell proliferation, growth, survival, migration, and differentiation. Given its wide expression, EGFR has many functions in development and tissue homeostasis. Some of the cellular outcomes of EGFR signaling involve alterations of specific aspects of cellular metabolism, and alterations of cell metabolism are emerging as driving influences in many physiological and pathophysiological contexts. Here we review the mechanisms by which EGFR regulates cell metabolism, including by modulation of gene expression and protein function leading to control of glucose uptake, glycolysis, biosynthetic pathways branching from glucose metabolism, amino acid metabolism, lipogenesis, and mitochondrial function. We further examine how this regulation of cell metabolism by EGFR may contribute to cell proliferation and differentiation and how EGFR-driven control of metabolism can impact certain diseases and therapy outcomes.
    Keywords:  Cancer; Cell metabolism; Differentiation; Proliferation; Receptor signaling
    DOI:  https://doi.org/10.1016/j.bbamcr.2022.119359
  16. Front Oncol. 2022 ;12 982751
    Drosophila as a toolkit to tackle cancer and its metabolism.
    Hui Jiang, Taku Kimura, Han Hai, Ryodai Yamamura, Masahiro Sonoshita.
      Cancer is one of the most severe health problems worldwide accounting for the second leading cause of death. Studies have indicated that cancers utilize different metabolic systems as compared with normal cells to produce extra energy and substances required for their survival, which contributes to tumor formation and progression. Recently, the fruit fly Drosophila has been attracting significant attention as a whole-body model for elucidating the cancer mechanisms including metabolism. This tiny organism offers a valuable toolkit with various advantages such as high genetic conservation and similar drug response to mammals. In this review, we introduce flies modeling for cancer patient genotypes which have pinpointed novel therapeutic targets and drug candidates in the salivary gland, thyroid, colon, lung, and brain. Furthermore, we introduce fly models for metabolic diseases such as diabetes mellitus, obesity, and cachexia. Diabetes mellitus and obesity are widely acknowledged risk factors for cancer, while cachexia is a cancer-related metabolic condition. In addition, we specifically focus on two cancer metabolic alterations: the Warburg effect and redox metabolism. Indeed, flies proved useful to reveal the relationship between these metabolic changes and cancer. Such accumulating achievements indicate that Drosophila offers an efficient platform to clarify the mechanisms of cancer as a systemic disease.
    Keywords:  Drosophila; cancer; drug discovery; genetics; metabolic reprogramming
    DOI:  https://doi.org/10.3389/fonc.2022.982751
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