Valentino A, Calarco A, Di Salle A, Finicelli M, Crispi S, Calogero R A, Riccardo F, Sciarra A, Gentilucci A, Galderisi U, Margarucci S, Peluso G
Institute of Agro-environmental and Forest Biology, National Research Council, IBAF - CNR, Naples, Italy.
Institute of Bioscience and BioResources - CNR, Naples, Italy.
Oncogene. 2017 Oct 26;36(43):6030-6040. doi: 10.1038/onc.2017.216. Epub 2017 Jul 3.
Cancer cells reprogram their metabolism to maintain both viability and uncontrolled proliferation. Although an interplay between the genetic, epigenetic and metabolic rewiring in cancer is beginning to emerge, it remains unclear how this metabolic plasticity occurs. Here, we report that in prostate cancer cells (PCCs) microRNAs (miRNAs) greatly contribute to deregulation of mitochondrial fatty acid (FA) oxidation via carnitine system modulation. We provide evidence that the downregulation of hsa-miR-124-3p, hsa-miR-129-5p and hsa-miR-378 induced an increase in both expression and activity of CPT1A, CACT and CrAT in malignant prostate cells. Moreover, the analysis of human prostate cancer and prostate control specimens confirmed the aberrant expression of miR-124-3p, miR-129-5p and miR-378 in primary tumors. Forced expression of the miRNAs mentioned above affected tumorigenic properties, such as proliferation, migration and invasion, in PC3 and LNCaP cells regardless of their hormone sensitivity. CPT1A, CACT and CrAT overexpression allow PCCs to be more prone on FA utilization than normal prostate cells, also in the presence of high pyruvate concentration. Finally, the simultaneous increase of CPT1A, CACT and CrAT is fundamental for PCCs to sustain FA oxidation in the presence of heavy lipid load on prostate cancer mitochondria. Indeed, the downregulation of only one of these proteins reduces PCCs metabolic flexibility with the accumulation of FA-intermediate metabolites in the mitochondria. Together, our data implicate carnitine cycle as a primary regulator of adaptive metabolic reprogramming in PCCs and suggest new potential druggable pathways for prevention and treatment of prostate cancer.
癌细胞会对其新陈代谢进行重编程，以维持生存能力和不受控制的增殖。尽管癌症中基因、表观遗传和代谢重排之间的相互作用已开始显现，但这种代谢可塑性是如何发生的仍不清楚。在此，我们报告在前列腺癌细胞（PCCs）中，微小RNA（miRNAs）通过调节肉碱系统，极大地促成了线粒体脂肪酸（FA）氧化的失调。我们提供的证据表明，hsa-miR-124-3p、hsa-miR-129-5p和hsa-miR-378的下调导致恶性前列腺细胞中CPT1A、CACT和CrAT的表达及活性增加。此外，对人类前列腺癌和前列腺对照标本的分析证实了原发性肿瘤中miR-124-3p、miR-129-5p和miR-378的异常表达。上述miRNAs的强制表达影响了PC3和LNCaP细胞的致瘤特性，如增殖、迁移和侵袭，无论它们的激素敏感性如何。CPT1A、CACT和CrAT的过表达使PCCs比正常前列腺细胞更倾向于利用FA，即使在丙酮酸浓度较高的情况下也是如此。最后，CPT1A、CACT和CrAT的同时增加对于PCCs在前列腺癌线粒体存在大量脂质负荷的情况下维持FA氧化至关重要。事实上，仅下调这些蛋白中的一种就会降低PCCs的代谢灵活性，导致线粒体中FA中间代谢产物的积累。总之，我们的数据表明肉碱循环是PCCs适应性代谢重编程的主要调节因子，并为前列腺癌的预防和治疗提出了新的潜在可药物化途径。
