Arginine Methylation of MDH1 by CARM1 Inhibits Glutamine Metabolism and Suppresses Pancreatic Cancer

Wang, Yiping; Wei, Zhou; Wang, Jian; Huang, Xian; Zuo, Yongchun; Wang, Tian-Shi; Gao, Xue; Xu, Yingying; Zou, Shaowu; Liu, Yingbin; Cheng, Jinke; Lei, Qun-Ying

doi:10.1016/j.molcel.2016.09.028

Cited by 157 publications

(109 citation statements)

References 51 publications

Supporting

Mentioning

108

Contrasting

Order By: Relevance

“…Glutamine is a critical metabolite that participates in energy metabolism, redox homeostasis, nucleotide, and amino acid biosynthesis 22. Moreover, as a major tricarboxylic acid (TCA) cycle carbon source in cancerous cells, glutamine is necessary to support cancerous cells growth and proliferation 23. The frequently activate glutamine consumption in cancerous cells was further proved by our MSI assay.…”

Section: Functional Metabolites Based Molecular Histologymentioning

confidence: 70%

A Sensitive and Wide Coverage Ambient Mass Spectrometry Imaging Method for Functional Metabolites Based Molecular Histology

Sun

et al. 2018

Advanced Science

View full text Add to dashboard Cite

Histological examination with a deep link between functional metabolites and tissue structure and biofunctions will provide important in situ biochemical information, and then essentially reveal what has happened in tissue at the molecular level. However, due to the complexity and heterogeneity of tissue samples and the large number of metabolites, it is still a challenge to globally map the diverse metabolites, especially for those low‐abundance functional ones. Here, a sensitive air flow‐assisted desorption electrospray ionization mass spectrometry imaging method for the mapping of a broad range of metabolites is presented. It exhibits properties characteristic of wide coverage, high sensitivity, wide dynamic range, rapid analysis procedure, and high specificity for tissue metabolites imaging. More than 1500 metabolites, including cholines, polyamines, amino acids, carnitines, nucleosides, nucleotides, nitrogen bases, organic acids, carbohydrates, cholesterol sulfate, cholic acid, lipids, etc., can be visualized in an untargeted analysis. The distribution of metabolites shows good spatial match with tissue histological structure and biofunctions in heterogeneous rat kidney, rat brain, and human esophageal cancer tissue. This method possesses the ability to globally showcase the molecular processes in tissue, and provide an insightful way for structural and functional molecular recognition in histological examination, even for intraoperative decision‐making.

show abstract

Section: Functional Metabolites Based Molecular Histologymentioning

confidence: 70%

A Sensitive and Wide Coverage Ambient Mass Spectrometry Imaging Method for Functional Metabolites Based Molecular Histology

Sun

et al. 2018

Advanced Science

View full text Add to dashboard Cite

show abstract

“…However, TCGA database revealed MDH1 amplification in solid tumor models (Figure 4) suggesting that, unlike in cell culture models, the availability of substrate drives selection for MDH1 over-expression. A recent study also revealed MDH1 amplification and increased MDH1 activity in human PDAC samples(30). In demonstrating the importance of MDH1-mediated malate synthesis to cytosolic NAD regeneration in highly glycolytic cells, this study offers fresh insights into metabolic alterations aimed at meeting the demands of growth and division and highlights the need for alternative strategies to target the increased consumption and utilization of glucose in cancers.…”

Section: Discussionmentioning

confidence: 85%

“…The efficiency arises from the fact that malate can be further metabolized for biomass, energy generation or ROS control, whereas lactate is primarily secreted into the extracellular environment as waste. A recent study has also demonstrated the importance of MDH1 activity in KRAS driven pancreatic ductal carcinomas to control ROS by providing malate as a substrate for malic enzyme and NADPH production(30). Moreover, LDHA inhibition did not significantly repress growth in Jurkat cells unless MDH1 was knocked out.…”

Section: Discussionmentioning

confidence: 99%

Cytosolic malate dehydrogenase activity helps support glycolysis in actively proliferating cells and cancer

et al. 2017

View full text Add to dashboard Cite

Increased glucose consumption is a hallmark of cancer cells. The increased consumption and subsequent metabolism of glucose during proliferation creates the need for a constant supply of NAD, a co-factor in glycolysis. Regeneration of the NAD required to support enhanced glycolysis has been attributed to the terminal glycolytic enzyme, lactate dehydrogenase (LDH). However, loss of glucose carbons to biosynthetic pathways early in glycolysis reduces the carbon supply to LDH. Thus, alternative routes for NAD regeneration must exist to support the increased glycolytic rate while allowing for the diversion of glucose to generate biomass and support proliferation. Here we demonstrate, using a variety of cancer cell lines as well as activated primary T cells, that cytosolic malate dehydrogenase 1 (MDH1) is an alternative to LDH as a supplier of NAD. Moreover, our results indicate that MDH1 generates malate with carbons derived from glutamine, thus enabling utilization of glucose carbons for glycolysis and for biomass. Amplification of MDH1 occurs at an impressive frequency in human tumors and correlates with poor prognosis. Together, our findings suggest proliferating cells rely on both MDH1 and LDH to replenish cytosolic NAD and therapies designed at targeting glycolysis must consider both dehydrogenases.

show abstract

“…Thus, the role of ACSL1, carbonic anhydrase, and SCD1 in cancer are all supported by literature. Although MDH1 inactivation inhibits pancreatic cancer growth by suppressing glutamine metabolism 41 , the role of MDH1 in de novo fatty acid synthesis has not been previously studied, and may be a potential new target to manipulate fatty acid metabolism for prostate cancer treatment.…”

Section: Resultsmentioning

confidence: 99%

Spatial modeling of prostate cancer metabolic gene expression reveals extensive heterogeneity and selective vulnerabilities

Wang

Ruzzo

2020

Sci Rep

View full text Add to dashboard Cite

Spatial heterogeneity is a fundamental feature of the tumor microenvironment (TME), and tackling spatial heterogeneity in neoplastic metabolic aberrations is critical for tumor treatment. Genomescale metabolic network models have been used successfully to simulate cancer metabolic networks. However, most models use bulk gene expression data of entire tumor biopsies, ignoring spatial heterogeneity in the TME. To account for spatial heterogeneity, we performed spatially-resolved metabolic network modeling of the prostate cancer microenvironment. We discovered novel malignantcell-specific metabolic vulnerabilities targetable by small molecule compounds. We predicted that inhibiting the fatty acid desaturase SCD1 may selectively kill cancer cells based on our discovery of spatial separation of fatty acid synthesis and desaturation. We also uncovered higher prostaglandin metabolic gene expression in the tumor, relative to the surrounding tissue. Therefore, we predicted that inhibiting the prostaglandin transporter SLCO2A1 may selectively kill cancer cells. Importantly, SCD1 and SLCO2A1 have been previously shown to be potently and selectively inhibited by compounds such as CAY10566 and suramin, respectively. We also uncovered cancer-selective metabolic liabilities in central carbon, amino acid, and lipid metabolism. Our novel cancer-specific predictions provide new opportunities to develop selective drug targets for prostate cancer and other cancers where spatial transcriptomics datasets are available.Cancer cells reprogram their metabolism to fulfill the energetic and biosynthetic needs of proliferation, invasion and migration 1 . This is exemplified in prostate cancer, the second most common cancer in American men after melanoma 2 . Previous studies have uncovered profound metabolic dysregulation in multiple pathways, particularly in fatty acid and lipid metabolism 3,4 . Discovering novel cancer-specific metabolic aberrations has significant translational applications, because cancer-associated metabolic dysfunctions can be exploited to advance cancer detection (e.g., 18 F-FDG (Fludeoxyglucose) imaging based on elevated glycolysis in cancer 5 ) and treatment (e.g., L-asparaginase in treating acute lymphoblastic leukemia 6 ).Cancer metabolic reprograming is profoundly impacted by spatial heterogeneity, a fundamental feature of the tumor microenvironment (TME) 7 . Heterogeneous distributions of blood vessels and stromal tissues create uneven spatial gradients of nutrients and metabolic byproducts, which significantly shape the phenotypes of many cell types in the TME 8 . Recent technologies, such as spatial transcriptomics 9,10 and Slide-seq 11 have enabled transcriptomic profiling of hundreds of locations within tissue sections with high spatial resolution (2-100 μm), and have been used to study multiple types of malignancies, including prostate cancer, breast cancer, pancreatic cancer, and melanoma 9,10,12-14 . These spatially-resolved datasets provide novel opportunities to dissect spatial metabolic heterogeneity i...

show abstract

Arginine Methylation of MDH1 by CARM1 Inhibits Glutamine Metabolism and Suppresses Pancreatic Cancer

Cited by 157 publications

References 51 publications

A Sensitive and Wide Coverage Ambient Mass Spectrometry Imaging Method for Functional Metabolites Based Molecular Histology

A Sensitive and Wide Coverage Ambient Mass Spectrometry Imaging Method for Functional Metabolites Based Molecular Histology

Cytosolic malate dehydrogenase activity helps support glycolysis in actively proliferating cells and cancer

Spatial modeling of prostate cancer metabolic gene expression reveals extensive heterogeneity and selective vulnerabilities

Contact Info

Product

Resources

About