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.
Cell Death Dis. 2024 Jul 18;15(7):513. doi: 10.1038/s41419-024-06893-2.
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.
代谢重编程和能量重塑是癌症的标志，它们推动疾病进展并促进治疗逃逸。氧化磷酸化的重塑和增强的脂肪生成以前被认为是前列腺癌（PCa）的关键代谢特征。最近，在高级别前列腺肿瘤中发现了依赖琥珀酸的线粒体重编程，以及与支链氨基酸（BCAA）分解代谢相关的酶的上调。在这项研究中，我们假设支链氨基酸（特别是缬氨酸）的降解可能在琥珀酸线粒体池的补充以及维持细胞内脂质代谢方面发挥关键作用。通过抑制 BCAA 的可用性，我们报告脂质含量明显降低，这强烈表明 BCAA 是 PCa 中重要的生脂燃料。这项工作还揭示了一种新的补偿机制，即脂肪酸摄取增加以响应细胞外缬氨酸缺乏。通过抑制 3-羟基异丁酰辅酶 A 水解酶（HIBCH）来抑制缬氨酸降解会导致恶性前列腺细胞增殖选择性减少、细胞内琥珀酸减少和细胞呼吸受损。与包含下一代测序、代谢组学和高内涵定量单细胞成像的综合多组学研究相结合，我们的工作强调了一种新的治疗靶点，用于选择性抑制 PCa 中的代谢重编程。
