Regulation of Tumor Initiation by the Mitochondrial Pyruvate Carrier.
cancer metabolism
carbohydrate metabolism
colon cancer
mitochondria
pyruvate metabolism
stem cell metabolism
tumor initiation
Journal
Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170
Informations de publication
Date de publication:
04 02 2020
04 02 2020
Historique:
received:
04
03
2019
revised:
03
09
2019
accepted:
05
11
2019
pubmed:
10
12
2019
medline:
2
6
2021
entrez:
10
12
2019
Statut:
ppublish
Résumé
Although metabolic adaptations have been demonstrated to be essential for tumor cell proliferation, the metabolic underpinnings of tumor initiation are poorly understood. We found that the earliest stages of colorectal cancer (CRC) initiation are marked by a glycolytic metabolic signature, including downregulation of the mitochondrial pyruvate carrier (MPC), which couples glycolysis and glucose oxidation through mitochondrial pyruvate import. Genetic studies in Drosophila suggest that this downregulation is required because hyperplasia caused by loss of the Apc or Notch tumor suppressors in intestinal stem cells can be completely blocked by MPC overexpression. Moreover, in two distinct CRC mouse models, loss of Mpc1 prior to a tumorigenic stimulus doubled the frequency of adenoma formation and produced higher grade tumors. MPC loss was associated with a glycolytic metabolic phenotype and increased expression of stem cell markers. These data suggest that changes in cellular pyruvate metabolism are necessary and sufficient to promote cancer initiation.
Identifiants
pubmed: 31813825
pii: S1550-4131(19)30609-6
doi: 10.1016/j.cmet.2019.11.002
pmc: PMC7004878
mid: NIHMS1543505
pii:
doi:
Substances chimiques
Mitochondrial Membrane Transport Proteins
0
Pyruvic Acid
8558G7RUTR
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
284-300.e7Subventions
Organisme : NIGMS NIH HHS
ID : R01 GM122778
Pays : United States
Organisme : NCI NIH HHS
ID : F30 CA225110
Pays : United States
Organisme : Howard Hughes Medical Institute
Pays : United States
Organisme : NIH HHS
ID : P40 OD018537
Pays : United States
Organisme : NCI NIH HHS
ID : K00 CA212445
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK091317
Pays : United States
Organisme : NHLBI NIH HHS
ID : T32 HL007576
Pays : United States
Organisme : NIDDK NIH HHS
ID : T32 DK110966
Pays : United States
Organisme : NIH HHS
ID : S10 OD016232
Pays : United States
Organisme : NIH HHS
ID : S10 OD018210
Pays : United States
Organisme : NCI NIH HHS
ID : R00 CA215307
Pays : United States
Organisme : NIDDK NIH HHS
ID : U54 DK110858
Pays : United States
Organisme : NICHD NIH HHS
ID : T32 HD007491
Pays : United States
Organisme : NIH HHS
ID : S10 OD021505
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA228346
Pays : United States
Informations de copyright
Copyright © 2019 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of Interests The University of Utah has filed a patent related to the mitochondrial pyruvate carrier, of which J.R. and C.S.T. are listed as co-inventors. All other authors declare no competing interests.
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