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Ketogenic HMG‐CoA lyase and its product β‐hydroxybutyrate promote pancreatic cancer progression
Ketogenic HMG‐CoA lyase and its product β‐hydroxybutyrate promote pancreatic cancer progression
- Source :
- EMBO Journal, EMBO Journal, 2022, ⟨10.15252/embj.2021110466⟩, The EMBO journal, vol 41, iss 9, EMBO J
- Publication Year :
- 2022
- Publisher :
- HAL CCSD, 2022.
-
Abstract
- 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.
- Subjects :
- pancreatic cancer
[SDV.CAN]Life Sciences [q-bio]/Cancer
Ketone Bodies
Medical and Health Sciences
General Biochemistry, Genetics and Molecular Biology
Mice
β-hydroxybutyrate
Rare Diseases
Information and Computing Sciences
Animals
metastasis
2.1 Biological and endogenous factors
Aetiology
Molecular Biology
Pancreas
ComputingMilieux_MISCELLANEOUS
Cancer
Nutrition
General Immunology and Microbiology
3-Hydroxybutyric Acid
General Neuroscience
Oxo-Acid-Lyases
Articles
HMGCL
Biological Sciences
Pancreatic Neoplasms
Digestive Diseases
Developmental Biology
Subjects
Details
- Language :
- English
- ISSN :
- 02614189 and 14602075
- Database :
- OpenAIRE
- Journal :
- EMBO Journal, EMBO Journal, 2022, ⟨10.15252/embj.2021110466⟩, The EMBO journal, vol 41, iss 9, EMBO J
- Accession number :
- edsair.doi.dedup.....402d390310382a7d2b9d332eef585cf9
- Full Text :
- https://doi.org/10.15252/embj.2021110466⟩