Bagnoli Marina, Granata Anna, Nicoletti Roberta, Krishnamachary Balaji, Bhujwalla Zaver M, Canese Rossella, Podo Franca, Canevari Silvana, Iorio Egidio, Mezzanzanica Delia
Unit of Molecular Therapies, Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale dei Tumori , Milan , Italy.
Russell H. Morgan Department of Radiology and Radiological Science, Division of Cancer Imaging Research, In Vivo Cellular and Molecular Imaging Center, The Johns Hopkins University School of Medicine , Baltimore, MD , USA.
Front Oncol. 2016 Jun 22;6:153. doi: 10.3389/fonc.2016.00153. eCollection 2016.
Compared with normal differentiated cells, cancer cells require a metabolic reprograming to support their high proliferation rates and survival. Aberrant choline metabolism is a fairly new metabolic hallmark reflecting the complex reciprocal interactions between oncogenic signaling and cellular metabolism. Alterations of the involved metabolic network may be sustained by changes in activity of several choline transporters as well as of enzymes such as choline kinase-alpha (ChoK-α) and phosphatidylcholine-specific phospholipases C and D. Of note, the net outcome of these enzymatic alterations is an increase of phosphocholine and total choline-containing compounds, a "cholinic phenotype" that can be monitored in cancer by magnetic resonance spectroscopy. This review will highlight the molecular basis for targeting this pathway in epithelial ovarian cancer (EOC), a highly heterogeneous and lethal malignancy characterized by late diagnosis, frequent relapse, and development of chemoresistance. Modulation of ChoK-α expression impairs only EOC but not normal ovarian cells, thus supporting the hypothesis that "cholinic phenotype" is a peculiar feature of transformed cells and indicating ChoK-α targeting as a novel approach to improve efficacy of standard EOC chemotherapeutic treatments.
与正常分化细胞相比，癌细胞需要进行代谢重编程以支持其高增殖率和存活。异常胆碱代谢是一个相当新的代谢特征，反映了致癌信号与细胞代谢之间复杂的相互作用。所涉及的代谢网络的改变可能由几种胆碱转运蛋白以及胆碱激酶α（ChoK-α）和磷脂酰胆碱特异性磷脂酶C和D等酶的活性变化所维持。值得注意的是，这些酶促改变的最终结果是磷酸胆碱和总含胆碱化合物增加，这是一种“胆碱表型”，可通过磁共振波谱在癌症中进行监测。本综述将重点介绍在上皮性卵巢癌（EOC）中靶向该途径的分子基础，EOC是一种高度异质性和致命性的恶性肿瘤，其特征为诊断晚、频繁复发和化疗耐药的发生。ChoK-α表达的调节仅损害EOC细胞而不损害正常卵巢细胞，因此支持了“胆碱表型”是转化细胞的一个特殊特征这一假设，并表明靶向ChoK-α是提高标准EOC化疗治疗疗效的一种新方法。
