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Ketogenic HMG-CoA lyase and its product β-hydroxybutyrate promote pancreatic cancer progression. | LitMetric

AI Article Synopsis

  • Pancreatic ductal adenocarcinoma (PDA) tumor cells adapt their metabolism to thrive under low oxygen and nutrient conditions, turning to ketone bodies as an alternative energy source.
  • The study finds that β-hydroxybutyrate (βOHB) enhances PDA growth by promoting ketogenesis through the activation of enzymes like HMGCL, which is significantly altered in PDA compared to normal pancreas tissue.
  • Targeting HMGCL could reduce tumor growth and invasiveness, suggesting a potential therapeutic pathway to combat PDA progression while βOHB appears to enhance metastasis to the liver.

Article 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC9058543PMC
http://dx.doi.org/10.15252/embj.2021110466DOI Listing

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