Distinctive from their normal counterparts, cancer cells exhibit unique metabolic dependencies on glutamine to fuel anabolic processes. Specifically, pancreatic ductal adenocarcinoma (PDAC) cells rely on an unconventional metabolic pathway catalyzed by aspartate aminotransferase, malate dehydrogenase 1 (MDH1), and malic enzyme 1 to rewire glutamine metabolism and support nicotinamide adenine dinucleotide phosphate (NADPH) production. Here, we report that methylation on arginine 248 (R248) negatively regulates MDH1. Protein arginine methyltransferase 4 (PRMT4/CARM1) methylates and inhibits MDH1 by disrupting its dimerization. Knockdown of MDH1 represses mitochondria respiration and inhibits glutamine metabolism, which sensitizes PDAC cells to oxidative stress and suppresses cell proliferation. Meanwhile, re-expression of wild-type MDH1, but not its methylation-mimetic mutant, protects cells from oxidative injury and restores cell growth and clonogenic activity. Importantly, MDH1 is hypomethylated at R248 in clinical PDAC samples. Our study reveals that arginine methylation of MDH1 by CARM1 regulates cellular redox homeostasis and suppresses glutamine metabolism of pancreatic cancer.
Download full-text PDF |
Source |
|---|---|
| http://dx.doi.org/10.1016/j.molcel.2016.09.028 | DOI Listing |
Publication Analysis
Top Keywords
Similar Publications
Metabolic Atlas of Human Eyelid Infiltrative Basal Cell Carcinoma.
Invest Ophthalmol Vis Sci
January 2025
State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Guangzhou, China.
Purpose: Eyelid infiltrative basal cell carcinoma (iBCC) is the most common malignant tumor affecting the ocular adnexa, but studies on metabolic changes within its microenvironment and heterogeneity at the tumor invasive area are limited. This study aims to analyze metabolic differences among iBCC cell types using single-cell and spatial metabolomics analysis and to examine metabolic environment at the tumor invasive area.
Methods: Single-cell transcriptomic data of human basal cell carcinoma (BCC) were clustered and visualized using Uniform Manifold Approximation and Projection.
The Balance of Ketoacids α-Ketoglutarate and α-Ketoglutaramate Reflects the Degree of the Development of Hepatoencephalopathy in Rats.
Int J Mol Sci
December 2024
Centre for Strategic Planning of FMBA of the Russian Federation, Pogodinskaya St., Bld. 10, 119121 Moscow, Russia.
Hepatoencephalopathy (HE) is a liver disease that can lead to brain pathology and the impairment of human cognitive abilities. The objective assessment of HE disease severity is difficult due to the lack of reliable diagnostic markers. This paper examines the background to the emergence of HE markers and provides a brief overview of research results indicating the diagnostic value of potential markers isolated from a wide range of metabolites analyzed.
View Article and Find Full Text PDFThe Search for a Universal Treatment for Defined and Mixed Pathology Neurodegenerative Diseases.
Int J Mol Sci
December 2024
Department of Biology, University of Toronto Mississauga, Mississauga, ON L5L 1C6, Canada.
The predominant neurodegenerative diseases, Alzheimer's disease, Parkinson's disease, dementia with Lewy Bodies, Huntington's disease, amyotrophic lateral sclerosis, and frontotemporal dementia, are rarely pure diseases but, instead, show a diversity of mixed pathologies. At some level, all of them share a combination of one or more different toxic biomarker proteins: amyloid beta (Aβ), phosphorylated Tau (pTau), alpha-synuclein (αSyn), mutant huntingtin (mHtt), fused in sarcoma, superoxide dismutase 1, and TAR DNA-binding protein 43. These toxic proteins share some common attributes, making them potentially universal and simultaneous targets for therapeutic intervention.
View Article and Find Full Text PDFProteomic Insights into the Regulatory Mechanisms of the Freezing Response in the Alpine Subnivale Plant .
Int J Mol Sci
December 2024
Ministry of Education Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou 730000, China.
Freezing temperatures impose significant constraints on plant growth and productivity. While cold tolerance mechanisms have been extensively studied in model species, the molecular basis of freezing tolerance in naturally adapted plants remains underexplored. , an alpine plant with a strong freezing tolerance, provides a valuable model for investigating these adaptive mechanisms.
View Article and Find Full Text PDFDirected Mutagenesis for Arginine Substitution of a Recombinant Lectin Disrupts Its Cytotoxic Activity.
Int J Mol Sci
December 2024
Facultad de Ciencias Naturales, Universidad Autónoma de Querétaro, Querétaro 76230, Querétaro, Mexico.
Recently, we reported that a recombinant Tepary bean () lectin (rTBL-1) induces apoptosis in colon cancer cell lines and that cytotoxicity was related to differential recognition of β1-6 branched -glycans. Sequencing analysis and resolution of the rTBL-1 3D structure suggest that glycan specificity could be strongly influenced by two arginine residues, R103 and R130, located in the carbohydrate binding pocket. The aim of this work was to determine the contribution of these residues towards cytotoxic activity.
View Article and Find Full Text PDFWant AI Summaries of new PubMed Abstracts delivered to your In-box?
Enter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!