bims-glucam 2023-02-05 papers

bims-glucam

Biomed News

on Glutamine cancer metabolism

Issue of 2023–02–05
seven papers selected by
Sreeparna Banerjee, Middle East Technical University

MicroRNA-376b-3p Suppresses Choroidal Neovascularization by Regulating Glutaminolysis in Endothelial Cells.
Glutamine synthetase: a tumor suppressor in hepatocellular carcinoma?
Hsa_circ_0005273 acts as a sponge of miR-509-3p to promote the malignant behaviors of breast cancer by regulating HMMR expression.
Slow TCA flux and ATP production in primary solid tumours but not metastases.
Immunometabolic factors contributing to obesity-linked hepatocellular carcinoma.
MYC disrupts transcriptional and metabolic circadian oscillations in cancer and promotes enhanced biosynthesis.
Integrated multi-omics reveals anaplerotic rewiring in methylmalonyl-CoA mutase deficiency.

Invest Ophthalmol Vis Sci. 2023 Jan 03. 64(1): 22

MicroRNA-376b-3p Suppresses Choroidal Neovascularization by Regulating Glutaminolysis in Endothelial Cells.

Yifan Feng, Liyang Wang, Chunqiong Dong, Xi Yang, Jing Wang, Xi Zhang, Yuanzhi Yuan, Jinhui Dai, Jinhai Huang, Fei Yuan.

Purpose: Choroidal neovascularization (CNV) is a common pathological change of various ocular diseases that causes serious damage to central vision. Accumulated evidence shows that microRNAs (miRNAs) are closely related with the regulation of endothelial metabolism, which plays crucial roles in angiogenesis. Here, we investigate the molecular mechanism underlying the regulation of endothelial glutamine metabolism by miR-376b-3p in the progression of CNV.
Methods: Human retinal microvascular endothelial cells (HRMECs) were transfected with control or miR-376b-3p mimics, and the expression of glutaminase 1 (GLS1), a rate-limiting enzyme in glutaminolysis, was detected by real-time PCR or Western blotting. The biological function and glutamine metabolism of transfected HRMECs were measured by related kits. Luciferase reporter assays were used to validate the CCAAT/enhancer-binding protein beta (CEBPB) was a target of miR-376b-3p. Chromatin immunoprecipitation and RNA immunoprecipitation assays were performed to verify the binding of CEBPB on the promoter region of GLS1. Fundus fluorescein angiography and immunofluorescence detected the effect of miR-376b-3p agomir on rat laser-induced CNV.
Results: The expression of miR-376b-3p was decreased, whereas GLS1 expression was increased in the retinal pigment epithelial-choroidal complexes of rats with CNV. HRMECs transfected with miR-376b-3p mimic showed inhibition of CEBPB, resulting in the inactivation of GLS1 transcription and glutaminolysis. Moreover, the miR-376b-3p mimic inhibited proliferation, migration and tube formation but promoted apoptosis in HRMECs, whereas these effects counteracted by α-ketoglutarate supplementation or transfection with CEBPB overexpression plasmid. Finally, the intravitreal administration of the miR-376b-3p agomir restrained CNV formation.
Conclusions: Collectively, miR-376b-3p is a suppressor of glutamine metabolism in endothelial cells that could be expected to become a therapeutic target for the treatment of CNV-related diseases.

DOI: https://doi.org/10.1167/iovs.64.1.22
J Mol Cell Biol. 2023 Feb 03. pii: mjad007. [Epub ahead of print]

Glutamine synthetase: a tumor suppressor in hepatocellular carcinoma?

Weiwei Dai, Wei-Xing Zong.

DOI: https://doi.org/10.1093/jmcb/mjad007
Thorac Cancer. 2023 Feb 02.

Hsa_circ_0005273 acts as a sponge of miR-509-3p to promote the malignant behaviors of breast cancer by regulating HMMR expression.

Yong Peng, Jianhua Cui, Kaiwen Ma, Xi Zhong.

   BACKGROUND: Breast cancer (BC) is a common malignant tumor that threatens the health of women worldwide. Hsa_circ_0005273 has been identified as a carcinogenic factor in some solid tumors, including BC. However, the molecular mechanism of circ_0005273 in BC is poorly defined.
METHODS: The expression of circ_0005273, miR-509-3p, and hyaluronan-mediated motility receptor (HMMR) mRNA in BC was detected by quantitative real-time polymerase chain reaction. Cell proliferation, migration, invasion, and apoptosis were detected by 5-ethynyl-2'-deoxyuridine, transwell, and flow cytometry assays. The glycolysis level was detected via specific kits. Western blot was used to detect protein expression. Binding between miR-509-3p and circ_0005273 or HMMR was also verified by dual-luciferase reporter, RNA pull-down, and RNA immunoprecipitation assays. Xenograft tumor model was used to detect tumor changes in mice, and immunohistochemistry assay was employed to detect Ki-67 abundance.
RESULTS: Circ_0005273 was increased in BC tissues and cells. Circ_0005273 knockdown might inhibit BC cell proliferation, migration, invasion, glutamine metabolism, and induce apoptosis. Circ_0005273 was a miR-509-3p, and the repression role of circ_0005273 absence on BC cell development was weakened by miR-509-3p inhibitor or HMMR overexpression. Circ_0005273 up-regulated the expression of HMMR by sponging miR-509-3p. Additionally, circ_0005273 silencing might hinder tumor growth in vivo.
CONCLUSION: Circ_0005273 knockdown might repress BC cell malignant behaviors by regulating the miR-509-3p/HMMR axis, which might provide a potential therapeutic target for BC.

Keywords:  BC; HMMR; circ_0005273; miR-509-3p; proliferation

DOI:  https://doi.org/10.1111/1759-7714.14809
Nature. 2023 Feb 01.

Slow TCA flux and ATP production in primary solid tumours but not metastases.

Caroline R Bartman, Daniel R Weilandt, Yihui Shen, Won Dong Lee, Yujiao Han, Tara TeSlaa, Connor S R Jankowski, Laith Samarah, Noel R Park, Victoria da Silva-Diz, Maya Aleksandrova, Yetis Gultekin, Argit Marishta, Lin Wang, Lifeng Yang, Asael Roichman, Vrushank Bhatt, Taijin Lan, Zhixian Hu, Xi Xing, Wenyun Lu, Shawn Davidson, Martin Wühr, Matthew G Vander Heiden, Daniel Herranz, Jessie Yanxiang Guo, Yibin Kang, Joshua D Rabinowitz.

Tissues derive ATP from two pathways-glycolysis and the tricarboxylic acid (TCA) cycle coupled to the electron transport chain. Most energy in mammals is produced via TCA metabolism1. In tumours, however, the absolute rates of these pathways remain unclear. Here we optimize tracer infusion approaches to measure the rates of glycolysis and the TCA cycle in healthy mouse tissues, Kras-mutant solid tumours, metastases and leukaemia. Then, given the rates of these two pathways, we calculate total ATP synthesis rates. We find that TCA cycle flux is suppressed in all five primary solid tumour models examined and is increased in lung metastases of breast cancer relative to primary orthotopic tumours. As expected, glycolysis flux is increased in tumours compared with healthy tissues (the Warburg effect2,3), but this increase is insufficient to compensate for low TCA flux in terms of ATP production. Thus, instead of being hypermetabolic, as commonly assumed, solid tumours generally produce ATP at a slower than normal rate. In mouse pancreatic cancer, this is accommodated by the downregulation of protein synthesis, one of this tissue's major energy costs. We propose that, as solid tumours develop, cancer cells shed energetically expensive tissue-specific functions, enabling uncontrolled growth despite a limited ability to produce ATP.

DOI: https://doi.org/10.1038/s41586-022-05661-6
Front Cell Dev Biol. 2022 ;10 1089124

Immunometabolic factors contributing to obesity-linked hepatocellular carcinoma.

May G Akl, Scott B Widenmaier.

  Hepatocellular carcinoma (HCC) is a major public health concern that is promoted by obesity and associated liver complications. Onset and progression of HCC in obesity is a multifactorial process involving complex interactions between the metabolic and immune system, in which chronic liver damage resulting from metabolic and inflammatory insults trigger carcinogenesis-promoting gene mutations and tumor metabolism. Moreover, cell growth and proliferation of the cancerous cell, after initiation, requires interactions between various immunological and metabolic pathways that provide stress defense of the cancer cell as well as strategic cell death escape mechanisms. The heterogenic nature of HCC in addition to the various metabolic risk factors underlying HCC development have led researchers to focus on examining metabolic pathways that may contribute to HCC development. In obesity-linked HCC, oncogene-induced modifications and metabolic pathways have been identified to support anabolic demands of the growing HCC cells and combat the concomitant cell stress, coinciding with altered utilization of signaling pathways and metabolic fuels involved in glucose metabolism, macromolecule synthesis, stress defense, and redox homeostasis. In this review, we discuss metabolic insults that can underlie the transition from steatosis to steatohepatitis and from steatohepatitis to HCC as well as aberrantly regulated immunometabolic pathways that enable cancer cells to survive and proliferate in the tumor microenvironment. We also discuss therapeutic modalities targeted at HCC prevention and regression. A full understanding of HCC-associated immunometabolic changes in obesity may contribute to clinical treatments that effectively target cancer metabolism.

Keywords:  NAFLD; hepatocellular carcinoma (HCC); immunometabolism; obesity; stress pathways

DOI:  https://doi.org/10.3389/fcell.2022.1089124
bioRxiv. 2023 Jan 04. pii: 2023.01.03.522637. [Epub ahead of print]

MYC disrupts transcriptional and metabolic circadian oscillations in cancer and promotes enhanced biosynthesis.

Rachel E DeRollo, Juliana Cazarin, Siti Noor Ain Binti Ahmad Shahidan, Jamison B Burchett, Daniel Mwangi, Saikumari Krishnaiah, Annie L Hsieh, Zandra E Walton, Rebekah Brooks, Stephano S Mello, Aalim M Weljie, Chi V Dang, Brian J Altman.

The molecular circadian clock, which controls rhythmic 24-hour oscillation of genes, proteins, and metabolites, is disrupted across many human cancers. Deregulated expression of MYC oncoprotein has been shown to alter expression of molecular clock genes, leading to a disruption of molecular clock oscillation across cancer types. It remains unclear what benefit cancer cells gain from suppressing clock oscillation, and how this loss of molecular clock oscillation impacts global gene expression and metabolism in cancer. We hypothesized that MYC suppresses oscillation of gene expression and metabolism to instead upregulate pathways involved in biosynthesis in a static, non-oscillatory fashion. To test this, cells from distinct cancer types with inducible MYC or the closely related N-MYC were examined, using detailed time-series RNA-sequencing and metabolomics, to determine the extent to which MYC activation disrupts global oscillation of genes, gene expression, programs, and metabolites. We focused our analyses on genes, pathways, and metabolites that changed in common across multiple cancer cell line models. We report here that MYC disrupted over 85% of oscillating genes, while instead promoting enhanced ribosomal and mitochondrial biogenesis and suppressed cell attachment pathways. Notably, when MYC is activated, biosynthetic programs that were formerly circadian flipped to being upregulated in an oscillation-free manner. Further, activation of MYC ablates the oscillation of nutrient transporter glycosylation while greatly upregulating transporter expression, cell surface localization, and intracellular amino acid pools. Finally, we report that MYC disrupts metabolite oscillations and the temporal segregation of amino acid metabolism from nucleotide metabolism. Our results demonstrate that MYC disruption of the molecular circadian clock releases metabolic and biosynthetic processes from circadian control, which may provide a distinct advantage to cancer cells.

DOI: https://doi.org/10.1101/2023.01.03.522637
Nat Metab. 2023 Jan;5(1): 80-95

Integrated multi-omics reveals anaplerotic rewiring in methylmalonyl-CoA mutase deficiency.

Patrick Forny, Ximena Bonilla, David Lamparter, Wenguang Shao, Tanja Plessl, Caroline Frei, Anna Bingisser, Sandra Goetze, Audrey van Drogen, Keith Harshman, Patrick G A Pedrioli, Cedric Howald, Martin Poms, Florian Traversi, Céline Bürer, Sarah Cherkaoui, Raphael J Morscher, Luke Simmons, Merima Forny, Ioannis Xenarios, Ruedi Aebersold, Nicola Zamboni, Gunnar Rätsch, Emmanouil T Dermitzakis, Bernd Wollscheid, Matthias R Baumgartner, D Sean Froese.

Methylmalonic aciduria (MMA) is an inborn error of metabolism with multiple monogenic causes and a poorly understood pathogenesis, leading to the absence of effective causal treatments. Here we employ multi-layered omics profiling combined with biochemical and clinical features of individuals with MMA to reveal a molecular diagnosis for 177 out of 210 (84%) cases, the majority (148) of whom display pathogenic variants in methylmalonyl-CoA mutase (MMUT). Stratification of these data layers by disease severity shows dysregulation of the tricarboxylic acid cycle and its replenishment (anaplerosis) by glutamine. The relevance of these disturbances is evidenced by multi-organ metabolomics of a hemizygous Mmut mouse model as well as through identification of physical interactions between MMUT and glutamine anaplerotic enzymes. Using stable-isotope tracing, we find that treatment with dimethyl-oxoglutarate restores deficient tricarboxylic acid cycling. Our work highlights glutamine anaplerosis as a potential therapeutic intervention point in MMA.

DOI: https://doi.org/10.1038/s42255-022-00720-8