Sphingomyelin and sphingomyelin synthase (SMS) in the malignant transformation of glioma cells and in 2-hydroxyoleic acid therapy
Sphingomyelin and sphingomyelin synthase (SMS) in the malignant transformation of glioma cells and in 2-hydroxyoleic acid therapy
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DOI：
10.1073/pnas.1115484108
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发表时间：
2011-12-06
影响因子：
11.1
通讯作者：
Escriba, Pablo V.
中科院分区：
文献类型：
--
作者：
Barcelo-Coblijn, Gwendolyn;Laura Martin, Maria;Escriba, Pablo V.
2-羟基油酸（2 OHOA）是一种有效的抗肿瘤化合物，其作用机制尚未完全阐明。在这里，我们表明，人类癌细胞有显着较低水平的鞘磷脂（SM）比非肿瘤（MRC-5）细胞。在这种情况下，2 OHOA处理强烈增加SM质量（4.6倍），恢复MRC-5细胞中发现的水平，同时观察到磷脂酰乙醇胺和磷脂酰胆碱的损失（分别为57%和30%）。SM质量的增加是由于SM酶（SMS）的快速和高度特异性激活。这种效应似乎对癌细胞具有特异性，因为它不影响非肿瘤MRC-5细胞。因此，低SM水平与产生癌细胞的致瘤性转化相关。SM积累发生在质膜上，并引起膜的全球秩序和模型膜中的脂筏包装的增加。这些修饰可以解释2 OHOA在参与细胞凋亡（Fas受体）或分化（Ras）的蛋白质定位中观察到的改变。重要的是，D 609抑制SMS减少了2 OHOA对细胞周期的影响。因此，我们认为SMS在肿瘤细胞中的活性调节是2 OHOA抗肿瘤机制中的关键上游事件，这也解释了其对癌细胞的特异性，其效力和缺乏不良副作用。最后，SMS的特异性激活解释了该化合物在癌细胞中触发细胞周期停滞、细胞分化和自噬或凋亡的能力。
The mechanism of action of 2-hydroxyoleic acid (2OHOA), a potent antitumor compound, has not yet been fully elucidated. Here, we show that human cancer cells have markedly lower levels of sphingomyelin (SM) than nontumor (MRC-5) cells. In this context, 2OHOA treatment strongly augments SM mass (4.6-fold), restoring the levels found in MRC-5 cells, while a loss of phosphatidylethanolamine and phosphatidylcholine is observed (57 and 30%, respectively). The increased SM mass was due to a rapid and highly specific activation of SM synthases (SMS). This effect appeared to be specific against cancer cells as it did not affect nontumor MRC-5 cells. Therefore, low SM levels are associated with the tumorigenic transformation that produces cancer cells. SM accumulation occurred at the plasma membrane and caused an increase in membrane global order and lipid raft packing in model membranes. These modifications would account for the observed alteration by 2OHOA in the localization of proteins involved in cell apoptosis (Fas receptor) or differentiation (Ras). Importantly, SMS inhibition by D609 diminished 2OHOA effect on cell cycle. Therefore, we propose that the regulation of SMS activity in tumor cells is a critical upstream event in 2OHOA antitumor mechanism, which also explains its specificity for cancer cells, its potency, and the lack of undesired side effects. Finally, the specific activation of SMS explains the ability of this compound to trigger cell cycle arrest, cell differentiation, and autophagy or apoptosis in cancer cells.