Title: Ceramide inhibition of MMP-2 expression and human cancer bronchial cell invasiveness involve decreased histone acetylation.

Authors: Debret, Romain; Brassart-Pasco, Sylvie; Lorin, Johanna; Martoriati, Alain; Deshorgue, Aurelie; Maquart, François-Xavier; Hornebeck, William; Rahman, Irfan; Antonicelli, Frank

Published In Biochim Biophys Acta, (2008 Oct)

Abstract: 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(R) 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.

PubMed ID: 18598724

MeSH Terms: No MeSH terms associated with this publication