Long chain ceramides and very long chain ceramides have opposite effects on human breast and colon cancer cell growth

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• 作者：Daniela Hartmann^a ; ¹ ; Jessica Lucks^a ; ¹ ; Sina Fuchs^a ; Susanne Schiffmann^a ; Yannick Schreiber^a ; Nerea Ferreiró ; s^a ; Jennifer Merkens^b ; Rolf Marschalek^b ; Gerd Geisslinger^a ; Sabine Grö ; sch^a ; ^{groesch@em.uni-frankfurt.de}
• 关键词：Cer ; ceramide ; dhCer ; dihydroceramide ; CerS(s) ; ceramide synthase(s) ; DES ; dihydroceramide desaturase ; GCS ; glucosylceramide synthase ; KSR ; 3-ketosphinganine reductase ; SMS ; sphingomyelin synthase ; SMase ; sphingomyelinase ; Sph1P ; sphingosine-1-phosphate
• 刊名：The International Journal of Biochemistry and Cell Biology
• 出版年：2012
• 出版时间：April, 2012
• 年：2012
• 卷：44
• 期：4
• 页码：620-628
• 全文大小：1193 K

文摘

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.