title: Ceramide inhibition of MMP-2 expression and human cancer bronchial cell invasiveness involve decreased histone acetylation.
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.
authors.affiliation: Laboratoire de Biochimie, Université de REIMS Champagne-Ardenne, CNRS UMR-6237, 51095 REIMS Cedex, France.
authors.forename: Romain
authors.initials: R
authors.lastname: Debret
authors.forename: Sylvie
authors.initials: S
authors.lastname: Brassart-Pasco
authors.forename: Johanna
authors.initials: J
authors.lastname: Lorin
authors.forename: Alain
authors.initials: A
authors.lastname: Martoriati
authors.forename: Aurelie
authors.initials: A
authors.lastname: Deshorgue
authors.forename: François-Xavier
authors.initials: FX
authors.lastname: Maquart
authors.forename: William
authors.initials: W
authors.lastname: Hornebeck
authors.forename: Irfan
authors.initials: I
authors.lastname: Rahman
authors.forename: Frank
authors.initials: F
authors.lastname: Antonicelli
mesh_terms: D000107:Acetylation / Q000187:drug effects; D001984:Bronchial Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D002460:Cell Line; D002518:Ceramides / Q000494:pharmacology*; D015536:Down-Regulation / Q000187:drug effects; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D006657:Histones / Q000378:metabolism*; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000235:genetics / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D002518:Ceramides; D006657:Histones; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D017382:Reactive Oxygen Species; D020778:Matrix Metalloproteinase 2