Ceramide inhibition of MMP-2 expression and human cancer bronchial cell invasiveness involve decreased histone acetylation
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- 作者：Romain Debret ; Sylvie Brassart-Pasco ; Johanna Lorin ; Alain Martoriati ; Aurelie Deshorgue ; Franç ; ois-Xavier Maquart ; William Hornebeck ; Irfan Rahman ; Frank Antonicelli
- 关键词：MMP ; Invasion ; HDAC ; Ceramide ; Lung
- 刊名：Biochimica et Biophysica Acta (BBA)/Molecular Cell Research
- 出版年：2008
- 出版时间：October 2008
- 年：2008
- 卷：1783
- 期：10
- 页码：1718-1727
- 全文大小：1217 K
文摘
Ceramides have been proposed as potential therapeutic strategy with regard to their ability to induce cell death. We previously demonstrated that C2-ceramide generated apoptosis in bronchocarcinoma BZR cells. We here investigated whether ceramides also target other molecules involved in cell–cell or cell–matrix interactions during cancer progression. A SuperArray® analysis showed that ceramides modulate gene expression after 2 h. Among deregulated genes, we observed an inhibition of the transcript coding for the pro-metastatic enzyme MMP-2. The pharmacological inhibitor of caspases cascade, ZVAD-fmk, did not prevent C2-ceramide-induced down-regulation of MMP-2 ruling out apoptosis as a mediator of this event, whereas inhibition of oxidative stress using NAC confirmed a role for ROS. This effect of C2-ceramide was associated with changes in histone H3 acetylation. However, although histone deacetylase inhibitors are also currently under investigation for their anti-tumor activity, we demonstrated here that a combined treatment with trichostatin A abrogated both MMP-2 down-regulation and reduced invasive properties elicited by C2-ceramide alone. Hence, this study demonstrates that besides its apoptotic effect, C2-ceramide also exhibits anti-invasive properties, showing a dual beneficial effect against cancer progression, but casts some doubt on the use of HDAC inhibitors as combined treatment with drugs that trigger the ceramide pathway.