Ceramide inhibition of MMP-2 expression and human cancer bronchial cell invasiveness involve decreased histone acetylation.
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.
Debret
Romain
R
Laboratoire de Biochimie, Université de REIMS Champagne-Ardenne, CNRS UMR-6237, 51095 REIMS Cedex, France.
Brassart-Pasco
Sylvie
S
Lorin
Johanna
J
Martoriati
Alain
A
Deshorgue
Aurelie
A
Maquart
François-Xavier
FX
Hornebeck
William
W
Rahman
Irfan
I
Antonicelli
Frank
F
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
D002518:Ceramides; D006657:Histones; D061965:Matrix Metalloproteinase Inhibitors; D011480:Protease Inhibitors; D017382:Reactive Oxygen Species; D020778:Matrix Metalloproteinase 2