Targeting valine catabolism to inhibit metabolic reprogramming in prostate cancer.
Journal
Cell death & disease
ISSN: 2041-4889
Titre abrégé: Cell Death Dis
Pays: England
ID NLM: 101524092
Informations de publication
Date de publication:
18 Jul 2024
18 Jul 2024
Historique:
received:
24
01
2024
accepted:
05
07
2024
revised:
04
07
2024
medline:
19
7
2024
pubmed:
19
7
2024
entrez:
18
7
2024
Statut:
epublish
Résumé
Metabolic reprogramming and energetic rewiring are hallmarks of cancer that fuel disease progression and facilitate therapy evasion. The remodelling of oxidative phosphorylation and enhanced lipogenesis have previously been characterised as key metabolic features of prostate cancer (PCa). Recently, succinate-dependent mitochondrial reprogramming was identified in high-grade prostate tumours, as well as upregulation of the enzymes associated with branched-chain amino acid (BCAA) catabolism. In this study, we hypothesised that the degradation of the BCAAs, particularly valine, may play a critical role in anapleurotic refuelling of the mitochondrial succinate pool, as well as the maintenance of intracellular lipid metabolism. Through the suppression of BCAA availability, we report significantly reduced lipid content, strongly indicating that BCAAs are important lipogenic fuels in PCa. This work also uncovered a novel compensatory mechanism, whereby fatty acid uptake is increased in response to extracellular valine deprivation. Inhibition of valine degradation via suppression of 3-hydroxyisobutyryl-CoA hydrolase (HIBCH) resulted in a selective reduction of malignant prostate cell proliferation, decreased intracellular succinate and impaired cellular respiration. In combination with a comprehensive multi-omic investigation that incorporates next-generation sequencing, metabolomics, and high-content quantitative single-cell imaging, our work highlights a novel therapeutic target for selective inhibition of metabolic reprogramming in PCa.
Identifiants
pubmed: 39025852
doi: 10.1038/s41419-024-06893-2
pii: 10.1038/s41419-024-06893-2
doi:
Substances chimiques
Valine
HG18B9YRS7
Amino Acids, Branched-Chain
0
Succinic Acid
AB6MNQ6J6L
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
513Informations de copyright
© 2024. The Author(s).
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