Ketogenic HMG-CoA lyase and its product β-hydroxybutyrate promote pancreatic cancer progression.
HMGCL
ketone bodies
metastasis
pancreatic cancer
β-hydroxybutyrate
Journal
The EMBO journal
ISSN: 1460-2075
Titre abrégé: EMBO J
Pays: England
ID NLM: 8208664
Informations de publication
Date de publication:
02 05 2022
02 05 2022
Historique:
revised:
18
02
2022
received:
29
12
2021
accepted:
24
02
2022
pubmed:
22
3
2022
medline:
4
5
2022
entrez:
21
3
2022
Statut:
ppublish
Résumé
Pancreatic ductal adenocarcinoma (PDA) tumor cells are deprived of oxygen and nutrients and therefore must adapt their metabolism to ensure proliferation. In some physiological states, cells rely on ketone bodies to satisfy their metabolic needs, especially during nutrient stress. Here, we show that PDA cells can activate ketone body metabolism and that β-hydroxybutyrate (βOHB) is an alternative cell-intrinsic or systemic fuel that can promote PDA growth and progression. PDA cells activate enzymes required for ketogenesis, utilizing various nutrients as carbon sources for ketone body formation. By assessing metabolic gene expression from spontaneously arising PDA tumors in mice, we find HMG-CoA lyase (HMGCL), involved in ketogenesis, to be among the most deregulated metabolic enzymes in PDA compared to normal pancreas. In vitro depletion of HMGCL impedes migration, tumor cell invasiveness, and anchorage-independent tumor sphere compaction. Moreover, disrupting HMGCL drastically decreases PDA tumor growth in vivo, while βOHB stimulates metastatic dissemination to the liver. These findings suggest that βOHB increases PDA aggressiveness and identify HMGCL and ketogenesis as metabolic targets for limiting PDA progression.
Identifiants
pubmed: 35307861
doi: 10.15252/embj.2021110466
pmc: PMC9058543
doi:
Substances chimiques
Ketone Bodies
0
Oxo-Acid-Lyases
EC 4.1.3.-
3-hydroxy-3-methylglutaryl-coenzyme A lyase
EC 4.1.3.4
3-Hydroxybutyric Acid
TZP1275679
Banques de données
GEO
['GSE127891', 'GSE61412']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e110466Subventions
Organisme : NHLBI NIH HHS
ID : T32 HL007633
Pays : United States
Organisme : NCI NIH HHS
ID : F30 CA183474
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA168653
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA014051
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA201276
Pays : United States
Organisme : NCI NIH HHS
ID : R35 CA242379
Pays : United States
Informations de copyright
© 2022 The Authors.
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