Long chain ceramides and very long chain ceramides have opposite effects on human breast and colon cancer cell growth
Long chain ceramides and very long chain ceramides have opposite effects on human breast and colon cancer cell growth
复制标题
DOI：
10.1016/j.biocel.2011.12.019
复制
发表时间：
2012-04-01
影响因子：
4
通讯作者：
Groesch, Sabine
中科院分区：
文献类型：
--
作者：
Hartmann, Daniela;Lucks, Jessica;Groesch, Sabine
神经酰胺是细胞内信号转导的关键分子，参与细胞凋亡、细胞衰老、细胞增殖、细胞生长和分化。它们是由神经酰胺合成酶(CERs)合成的。到目前为止，已经描述了六种不同的哺乳动物CER(CerS1-6)。最近，我们发现人乳腺癌组织中CerS2、4和6的活性增加，并且它们的产物神经酰胺C-16：0、C-24：0和C-24：1的生成增加。而且，这些增加与肿瘤的尊严显著相关。为了阐明这一观察结果的影响，我们通过在MCF-7(乳腺癌)和HCT-116(结肠癌)细胞中分别过表达神经酰胺合成酶2、4或6来操纵细胞神经酰胺水平。神经酰胺合成酶4和6的过表达增加了短链神经酰胺C-16：0、C-18：0和C-20：0的产生，而神经酰胺合成酶2的过表达对体内神经酰胺的产生没有影响，可能是由于底物的可获得性有限，因为外部加入超长链酰基-COAS导致超长链神经酰胺的显著上调。我们还发现，CerS4和6的上调导致细胞增殖抑制和诱导细胞凋亡，而CerS2的上调促进了细胞的增殖。根据我们的数据，我们认为不同链长的神经酰胺之间的不平衡是癌症进展的关键，而正常细胞需要超长和长链神经酰胺之间的平衡才能实现正常的生理。(C)2012爱思唯尔有限公司。保留所有权利。
Ceramides are known to be key players in intracellular signaling and are involved in apoptosis, cell senescence, proliferation, cell growth and differentiation. They are synthesized by ceramide synthases (CerS). So far, six different mammalian CerS (CerS1-6) have been described. Recently, we demonstrated that human breast cancer tissue displays increased activity of CerS2, 4, and 6, together with enhanced generation of their products, ceramides C-16:0, C-24:0, and C-24:1. Moreover, these increases were significantly associated with tumor dignity. To clarify the impact of this observation, we manipulated cellular ceramide levels by overexpressing ceramide synthases 2, 4 or 6 in MCF-7 (breast cancer) and HCT-116 (colon cancer) cells, respectively. Overexpression of ceramide synthases 4 and 6 elevated generation of short chain ceramides C-16:0, C-18:0 and C-20:0, while overexpression of ceramide synthase 2 had no effect on ceramide production in vivo, presumably due to limited substrate availability, because external addition of very long chain acyl-CoAs resulted in a significant upregulation of very long chain ceramides. We also demonstrated that upregulation of CerS4 and 6 led to the inhibition of cell proliferation and induction of apoptosis, whereas upregulation of CerS2 increased cell proliferation. On the basis of our data, we propose that a disequilibrium between ceramides of various chain length is crucial for cancer progression, while normal cells require an equilibrium between very long and long chain ceramides for normal physiology. (C) 2012 Elsevier Ltd. All rights reserved.