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Choline kinase alpha—Putting the ChoK-hold on tumor metabolism
Progress in Lipid Research ( IF 13.6 ) Pub Date : 2016-04-09 , DOI: 10.1016/j.plipres.2016.03.005
Sean P. Arlauckas , Anatoliy V. Popov , E. James Delikatny

It is well established that lipid metabolism is drastically altered during tumor development and response to therapy. Choline kinase alpha (ChoKα) is a key mediator of these changes, as it represents the first committed step in the Kennedy pathway of phosphatidylcholine biosynthesis and ChoKα expression is upregulated in many human cancers. ChoKα activity is associated with drug resistant, metastatic, and malignant phenotypes, and represents a robust biomarker and therapeutic target in cancer. Effective ChoKα inhibitors have been developed and have recently entered clinical trials. ChoKα's clinical relevance was, until recently, attributed solely to its production of second messenger intermediates of phospholipid synthesis. The recent discovery of a non-catalytic scaffolding function of ChoKα may link growth receptor signaling to lipid biogenesis and requires a reinterpretation of the design and validation of ChoKα inhibitors. Advances in positron emission tomography, magnetic resonance spectroscopy, and optical imaging methods now allow for a comprehensive understanding of ChoKα expression and activity in vivo. We will review the current understanding of ChoKα metabolism, its role in tumor biology and the development and validation of targeted therapies and companion diagnostics for this important regulatory enzyme. This comes at a critical time as ChoKα-targeting programs receive more clinical interest.



中文翻译:

胆碱激酶α—将ChoK保持在肿瘤代谢上

众所周知,在肿瘤发展和对治疗的反应过程中,脂质代谢会发生巨大变化。胆碱激酶α(ChoKα)是这些变化的关键介体,因为它代表了磷脂酰胆碱生物合成的肯尼迪途径中的第一个重要步骤,并且在许多人类癌症中ChoKα的表达上调。ChoKα活性与耐药性,转移性和恶性表型有关,代表了癌症中强大的生物标志物和治疗靶标。已经开发出有效的ChoKα抑制剂,并且最近已进入临床试验。直到最近,ChoKα的临床意义仍仅归因于其生产磷脂合成的第二信使中间体。ChoKα的非催化支架功能的最新发现可能将生长受体信号传导与脂质生物发生联系起来,需要重新解释ChoKα抑制剂的设计和验证。现在,正电子发射断层扫描,磁共振波谱和光学成像方法的进步使人们对ChoKα的表达和活性有了全面的了解。体内。我们将回顾当前对ChoKα代谢的理解,其在肿瘤生物学中的作用以及针对这种重要调节酶的靶向疗法和伴随诊断方法的开发和验证。这是在关键时刻,因为ChoKα靶向计划越来越受到临床关注。

更新日期:2016-04-09
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