PDF(Pubmed)
Abstract：
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.
摘要：
代谢重新编程和能量重新布线是癌症的标志，可以促进疾病进展并促进治疗逃避。氧化磷酸化的重塑和增强的脂肪生成先前已被表征为前列腺癌（PCa）的关键代谢特征。最近,琥珀酸依赖的线粒体重编程在高级别前列腺肿瘤中被发现，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BCAA的退化，特别是缬氨酸，可能在线粒体琥珀酸盐池的麻醉换气中起关键作用，以及维持细胞内脂质代谢。通过抑制BCAA可用性，我们报告脂质含量显着降低，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，从而增加脂肪酸摄取以响应细胞外缬氨酸剥夺。通过抑制3-羟基异丁酰辅酶A水解酶（HIBCH）抑制缬氨酸降解导致恶性前列腺细胞增殖的选择性减少，减少细胞内琥珀酸和受损的细胞呼吸。结合结合下一代测序的全面的多体研究，代谢组学，和高含量的定量单细胞成像，我们的工作强调了一种选择性抑制PCa代谢重编程的新型治疗靶点.
