Targeting valine catabolism to inhibit metabolic reprogramming in prostate cancer.

Autor: Bidgood CL; Queensland University of Technology (QUT), Australian Prostate Cancer Research Centre - Queensland, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Translational Research Institute, Brisbane, QLD, Australia. cl.bidgood@qut.edu.au., Philp LK; Queensland University of Technology (QUT), Australian Prostate Cancer Research Centre - Queensland, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Translational Research Institute, Brisbane, QLD, Australia., Rockstroh A; Queensland University of Technology (QUT), Australian Prostate Cancer Research Centre - Queensland, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Translational Research Institute, Brisbane, QLD, Australia., Lehman M; Queensland University of Technology (QUT), Australian Prostate Cancer Research Centre - Queensland, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Translational Research Institute, Brisbane, QLD, Australia.; University of British Columbia, Vancouver Prostate Centre, Department of Urologic Sciences, Vancouver, BC, Canada., Nelson CC; Queensland University of Technology (QUT), Australian Prostate Cancer Research Centre - Queensland, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Translational Research Institute, Brisbane, QLD, Australia., Sadowski MC; University of Bern, Institute for Tissue Medicine and Pathology, Bern, Switzerland., Gunter JH; Queensland University of Technology (QUT), Australian Prostate Cancer Research Centre - Queensland, Centre for Genomics and Personalised Health, School of Biomedical Sciences, Translational Research Institute, Brisbane, QLD, Australia. jennifer.gunter@qut.edu.au.
Jazyk: angličtina
Zdroj: Cell death & disease [Cell Death Dis] 2024 Jul 18; Vol. 15 (7), pp. 513. Date of Electronic Publication: 2024 Jul 18.
DOI: 10.1038/s41419-024-06893-2
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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