Journal article
Disrupting Mitochondrial Pyruvate Uptake Directs Glutamine into the TCA Cycle away from Glutathione Synthesis and Impairs Hepatocellular Tumorigenesis
Cell reports (Cambridge), Vol.28(10), pp.2608-2619.e6
09/03/2019
DOI: 10.1016/j.celrep.2019.07.098
PMCID: PMC6746334
PMID: 31484072
Abstract
Hepatocellular carcinoma (HCC) is a devastating cancer increasingly caused by non-alcoholic fatty liver disease (NAFLD). Disrupting the liver Mitochondrial Pyruvate Carrier (MPC) in mice attenuates NAFLD. Thus, we considered whether liver MPC disruption also prevents HCC. Here, we use the N-nitrosodiethylamine plus carbon tetrachloride model of HCC development to test how liver-specific MPC knock out affects hepatocellular tumorigenesis. Our data show that liver MPC ablation markedly decreases tumorigenesis and that MPC-deficient tumors transcriptomically downregulate glutathione metabolism. We observe that MPC disruption and glutathione depletion in cultured hepatomas are synthetically lethal. Stable isotope tracing shows that hepatocyte MPC disruption reroutes glutamine from glutathione synthesis into the tricarboxylic acid (TCA) cycle. These results support a model where inducing metabolic competition for glutamine by MPC disruption impairs hepatocellular tumorigenesis by limiting glutathione synthesis. These findings raise the possibility that combining MPC disruption and glutathione stress may be therapeutically useful in HCC and additional cancers.
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•The MPC is retained in HCC, supporting TCA cycle pyruvate metabolism•MPC disruption directs glutamine to the TCA cycle away from glutathione synthesis•Glutathione synthesis is diminished, impairing hepatocellular tumorigenesis
Tompkins et al. utilize stable glutamine isotope tracers in vivo and ex vivo to demonstrate hepatocyte MPC disruption increases TCA cycle glutamine utilization at the expense of glutathione synthesis and decreases hepatocellular tumorigenesis.
Details
- Title: Subtitle
- Disrupting Mitochondrial Pyruvate Uptake Directs Glutamine into the TCA Cycle away from Glutathione Synthesis and Impairs Hepatocellular Tumorigenesis
- Creators
- Sean C. Tompkins - Roy J. and Lucille A. Carver College of MedicineRyan D. Sheldon - University of IowaAdam J. Rauckhorst - University of IowaMaria F. Noterman - Roy J. and Lucille A. Carver College of MedicineShane R. Solst - University of IowaJane L. Buchanan - Roy J. and Lucille A. Carver College of MedicineKranti A. Mapuskar - University of IowaAlvin D. Pewa - University of IowaLawrence R. Gray - Roy J. and Lucille A. Carver College of MedicineLalita Oonthonpan - University of IowaArpit Sharma - Roy J. and Lucille A. Carver College of MedicineDiego A. Scerbo - Roy J. and Lucille A. Carver College of MedicineAdam J. Dupuy - University of IowaDouglas R. Spitz - University of IowaEric B. Taylor - Roy J. and Lucille A. Carver College of Medicine
- Resource Type
- Journal article
- Publication Details
- Cell reports (Cambridge), Vol.28(10), pp.2608-2619.e6
- DOI
- 10.1016/j.celrep.2019.07.098
- PMID
- 31484072
- PMCID
- PMC6746334
- NLM abbreviation
- Cell Rep
- ISSN
- 2211-1247
- eISSN
- 2211-1247
- Publisher
- Elsevier Inc
- Grant note
- DOI: 10.13039/100000002, name: NIH, award: R01 DK104998, R01 CA132962, R01 CA182804, P30 CA086862, GM007337, T32 HL007344, F32 DK116522, T32 HL007638, T32 DK112751, F32 DK101183, F31 NS106773, P30CA086862; DOI: 10.13039/100000041, name: American Diabetes Association, award: 1-18-PDF-060
- Language
- English
- Date published
- 09/03/2019
- Academic Unit
- Molecular Physiology and Biophysics; Anatomy and Cell Biology; Pathology; Radiation Oncology; Fraternal Order of Eagles Diabetes Research Center; Biochemistry and Molecular Biology
- Record Identifier
- 9984284342802771
Metrics
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