Stearoyl-CoA desaturase-1 mediated cell apoptosis in colorectal cancer by promoting ceramide synthesis.
Stearoyl-CoA desaturase-1 mediated cell apoptosis in colorectal cancer by promoting ceramide synthesis.
复制标题
硬脂酰辅酶A去饱和酶1通过促进神经酰胺合成介导结直肠癌细胞凋亡
DOI：
10.1038/srep19665
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发表时间：
2016-01-27
影响因子：
4.6
通讯作者：
Qiu Y
中科院分区：
文献类型：
--
作者：
Chen L;Ren J;Yang L;Li Y;Fu J;Li Y;Tian Y;Qiu F;Liu Z;Qiu Y
在许多肿瘤病变中，抑制硬脂酰辅酶a去饱和酶1 （SCD1）可有效抑制肿瘤细胞增殖并诱导细胞凋亡。然而，scd1介导的抗肿瘤作用机制尚不清楚。在此，我们报道了内脂信使神经酰胺在SCD1抑制调节的肿瘤命运中发挥关键作用。结直肠癌细胞的体外研究表明，抑制SCD1活性可促进线粒体功能障碍、活性氧（ROS）上调、线粒体跨膜电位改变和线粒体蛋白细胞色素c易位导致的细胞凋亡，而这些作用是通过诱导神经酰胺生物合成的细胞内神经酰胺信号介导的，而不是单纯的SFA积累。在异种移植结直肠癌小鼠的体内研究中发现，给药SCD1抑制剂A939可显著延缓肿瘤生长，而神经酰胺生物合成抑制剂l -环丝氨酸可逆转这一作用。这些结果描述了scd1介导的脂质途径和内神经酰胺生物合成途径的交叉对话，提示神经酰胺信号在scd1介导的抗肿瘤特性中的作用。
Inhibition of stearoyl-CoA desaturase 1 (SCD1) has been found to effectively suppress tumor cell proliferation and induce apoptosis in numerous neoplastic lesions. However, mechanism underlying SCD1-mediated anti-tumor effect has maintained unclear. Herein, we reported endo-lipid messenger ceramides played a critical role in tumor fate modulated by SCD1 inhibition.In vitrostudy in colorectal cancer cells demonstrated inhibition of SCD1 activity promoted apoptosis attributed to mitochondria dysfunctions, upregulation of reaction oxygen species (ROS), alteration of mitochondrial transmembrane potential and translocation of mitochondrial protein cytochrome C. While these effects were mediated by intracellular ceramide signals through induction of ceramide biosynthesis, rather than exclusive SFA accumulation.In vivostudy in xenograft colorectal cancer mice showed pharmacologic administration of SCD1 inhibitor A939 significantly delayed tumor growth, which was reversed by L-cycloserine, an inhibitor of ceramide biosynthesis. These results depicted the cross-talk of SCD1-mediated lipid pathway and endo-ceramide biosynthesis pathway, indicating roles of ceramide signals in SCD1-mediated anti-tumor property.