Regulation of ceramide synthases in tumor cells and their effects on proliferation and apoptosis

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Ceramides are important molecules of membranes and are known to be key players in intracellular signaling by targeting different proteins like kinases and phosphatases. They are synthesized by ceramide synthases (CerS). So far, six different mammalian CerS (CerS1-6) have been described, which differ in their tissue expression level and their specificity to produce ceramides of various chain length. Previously, it has been demonstrated that human breast cancer tissue displays increased activity of CerS 2, 4, and 6, together with enhanced generation of their products, ceramides C16:0, C24:0, and C24:1. In vitro, treatment of MCF-7 and MDA-MB-231 cells with estradiol led to an increase in mRNA-expression of CerS 2,4 and 6 but not to an similarly increase in ceramides. The same was true for colon carcinoma cells (HCT-116/Caco-2) treated with TGF-. Caco-2 cells demonstrated an enhanced CerS mRNA-expression level after TGF- treatment which could not be correlated to the ceramide levels in these cells. Furthermore, it could be demonstrated that overexpression of ceramide synthases 4 and 6 in MCF-7 (breast cancer) and HCT-116 (colon cancer) cells was accompanied by elevated generation of short chain ceramides C16:0, C18:0 and C20:0 and induction of apoptosis in these cells. While overexpression of ceramide synthase 2 led to an increase in C24:0- and C24:1-Cer production and promoted proliferation of these cells. In this follow-up application transcriptional, post-transcriptional as well as post-translational mechanisms should be investigated leading to the induction of CerS on expression or activity level after TGF-/estradiol treatment. Furthermore, by using specific inhibitors and molecular biological methods, the signaling pathways should be analysed, that are targeted by long chain or very long chain ceramides leading to apoptosis or enhances proliferation, respectively. At the end, these investigations should shed light on the question, if CerS are useful targets for the development of new chemo therapeutics.