Bernacchioni Caterina, Ghini Veronica, Cencetti Francesca, Japtok Lukasz, Donati Chiara, Bruni Paola, Turano Paola
Department of Biomedical, Clinical and Experimental Sciences, University of Florence, Italy.
CERM and Department of Chemistry, University of Florence, Italy.
Mol Oncol. 2017 May;11(5):517-533. doi: 10.1002/1878-0261.12048. Epub 2017 Mar 30.
Strong experimental evidence in animal and cellular models supports a pivotal role of sphingosine kinase-1 (SK1) in oncogenesis. In many human cancers, SK1 levels are upregulated and these increases are linked to poor prognosis in patients. Here, by employing untargeted NMR-based metabolomic profiling combined with functional validations, we report the crucial role of SK1 in the metabolic shift known as the Warburg effect in A2780 ovarian cancer cells. Indeed, expression of SK1 induced a high glycolytic rate, characterized by increased levels of lactate along with increased expression of the proton/monocarboxylate symporter MCT1, and decreased oxidative metabolism, associated with the accumulation of intermediates of the tricarboxylic acid cycle and reduction in CO production. Additionally, SK1-expressing cells displayed a significant increase in glucose uptake paralleled by GLUT3 transporter upregulation. The role of SK1 is not limited to the induction of aerobic glycolysis, affecting metabolic pathways that appear to support the biosynthesis of macromolecules. These findings highlight the role of SK1 signaling axis in cancer metabolic reprogramming, pointing out innovative strategies for cancer therapies.
动物和细胞模型中的有力实验证据支持鞘氨醇激酶-1（SK1）在肿瘤发生中起关键作用。在许多人类癌症中，SK1水平上调，且这些升高与患者预后不良相关。在此，通过采用基于非靶向核磁共振的代谢组学分析并结合功能验证，我们报告了SK1在A2780卵巢癌细胞中被称为瓦伯格效应的代谢转变中的关键作用。事实上，SK1的表达诱导了高糖酵解速率，其特征是乳酸水平升高以及质子/单羧酸转运体MCT1的表达增加，同时氧化代谢降低，这与三羧酸循环中间产物的积累和CO产生减少有关。此外，表达SK1的细胞葡萄糖摄取显著增加，同时GLUT3转运体上调。SK1的作用不仅限于诱导有氧糖酵解，还影响似乎支持大分子生物合成的代谢途径。这些发现突出了SK1信号轴在癌症代谢重编程中的作用，为癌症治疗指出了创新策略。
