文章：

恶性转化中的胆碱代谢

Choline metabolism in malignant transformation

原文发布日期：2011-11-17

DOI: 10.1038/nrc3162

类型: Review Article

开放获取: 否

要点：

1. Some of the levels of metabolic intermediates that are generated in choline phospholipid metabolism, particularly phosphocholine (PCho) and total choline (tCho), are elevated in cancer, and can be used for non-invasive detection in cancer diagnosis and staging by using magnetic resonance spectroscopy (MRS) or positron emission tomography (PET).
2. Several enzymes in choline metabolism, such as choline transporter-like protein 1 (CTL1), choline kinase-α (CHKα), CTP:phosphocholine cytidylyltransferase (CCT), phosphatidylcholine-specific phospholipase D (PC-PLD) and PC-PLC, are overexpressed and/or activated in cancer and can potentially be used as prognostic markers.
3. Overexpression and activation of choline cycle enzymes are mediated by oncogenic signalling via pathways such as the RAS and PI3K–AKT pathways, and by transcription factors associated with oncogenesis such as hypoxia-inducible factor 1 (HIF1). Recent studies point to a reciprocal interaction between choline cycle enzymes and oncogenic signalling, where modulation of the enzymes can contribute to enhancing oncogenic signalling.
4. The therapeutic response of tumours can be monitored non-invasively by MRS of the tCho signal because treatment with conventional chemotherapeutic agents results in a decrease of tCho levels in responding, but not in non-responding, tumours.
5. Inhibition of oncogenic signalling pathways with targeted anticancer drugs results in altered choline-containing metabolite levels. Therefore, these metabolites could provide downstream metabolic readouts of the effective inhibition of these pathways.
6. New molecularly targeted therapeutic opportunities arise from targeting choline cycle enzymes such as CHKα, which is currently being tested in Phase I clinical trials.

要点翻译：

1. 胆碱磷脂代谢过程中产生的某些代谢中间体水平——特别是磷酸胆碱（PCho）和总胆碱（tCho）——在癌症中会升高，这一特性可通过磁共振波谱（MRS）或正电子发射断层成像（PET）技术用于癌症诊断与分期的无创检测。
2. 胆碱代谢中的多种酶类，包括胆碱转运样蛋白1（CTL1）、胆碱激酶-α（CHKα）、CTP:磷酸胆碱胞苷酰转移酶（CCT）、磷脂酰胆碱特异性磷脂酶D（PC-PLD）及PC-PLC，在癌症中过度表达和/或被激活，有望作为预后标志物。
3. 胆碱循环酶的过度表达与激活受RAS和PI3K–AKT等通路的致癌信号传导调控，同时受缺氧诱导因子1（HIF1）等致癌相关转录因子调节。最新研究指出胆碱循环酶与致癌信号存在双向相互作用，调控这些酶可增强致癌信号传导。
4. 通过tCho信号的MRS可无创监测肿瘤的治疗反应：传统化疗药物治疗后，应答肿瘤的tCho水平会下降，而无应答肿瘤则保持不变。
5. 使用靶向抗癌药物抑制致癌信号通路会改变含胆碱代谢物水平，因此这些代谢物可为此类通路的有效抑制提供下游代谢读数。
6. 以胆碱循环酶（如目前正处于I期临床试验阶段的CHKα）为靶点，为开发新型分子靶向治疗策略提供了可能。

英文摘要：

Abnormal choline metabolism is emerging as a metabolic hallmark that is associated with oncogenesis and tumour progression. Following transformation, the modulation of enzymes that control anabolic and catabolic pathways causes increased levels of choline-containing precursors and breakdown products of membrane phospholipids. These increased levels are associated with proliferation, and recent studies emphasize the complex reciprocal interactions between oncogenic signalling and choline metabolism. Because choline-containing compounds are detected by non-invasive magnetic resonance spectroscopy (MRS), increased levels of these compounds provide a non-invasive biomarker of transformation, staging and response to therapy. Furthermore, enzymes of choline metabolism, such as choline kinase, present novel targets for image-guided cancer therapy.

摘要翻译： 

异常胆碱代谢正被视为一种与肿瘤发生和肿瘤进展相关的代谢标志。在细胞转化后，调控合成与分解代谢途径的酶发生改变，导致膜磷脂中含胆碱前体及其分解产物的水平升高。这些升高与细胞增殖有关，近期研究强调了致癌信号通路与胆碱代谢之间复杂的相互作用。由于含胆碱化合物可通过无创性磁共振波谱（MRS）检测，其水平升高为转化、分期及治疗反应提供了一种无创性生物标志物。此外，胆碱代谢相关酶（如胆碱激酶）成为影像引导癌症治疗的新靶点。

原文链接：

Choline metabolism in malignant transformation