Choline kinase alpha-Putting the ChoK-hold on tumor metabolism.
Choline kinase alpha-Putting the ChoK-hold on tumor metabolism.
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DOI：
10.1016/j.plipres.2016.03.005
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发表时间：
2016-07
影响因子：
13.6
通讯作者：
Delikatny EJ
中科院分区：
文献类型：
--
作者：
Arlauckas SP;Popov AV;Delikatny EJ
众所周知，脂质代谢在肿瘤发展和对治疗的反应期间急剧改变。胆碱激酶α（ChoKα）是这些变化的关键介质，因为它代表了磷脂酰胆碱生物合成肯尼迪途径中的第一个关键步骤，并且ChoKα表达在许多人类癌症中上调。ChoKα活性与耐药性、转移性和恶性表型相关，代表了癌症的一个强大的生物标志物和治疗靶点。有效的ChoKα抑制剂已被开发出来，最近已进入临床试验。直到最近，ChoKα的临床相关性仅归因于其产生磷脂合成的第二信使中间体。最近发现ChoKα的非催化支架功能可能将生长受体信号传导与脂质生物合成联系起来，需要重新解释ChoKα抑制剂的设计和验证。正电子发射断层扫描，磁共振光谱和光学成像方法的进步，现在允许全面了解体内ChoKα的表达和活性。我们将回顾目前对ChoKα代谢的理解，其在肿瘤生物学中的作用，以及这种重要调节酶的靶向治疗和伴随诊断的开发和验证。这是在一个关键时刻，因为ChoKα靶向计划受到更多的临床兴趣。
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.