The natural marine anhydrophytosphingosine, Jaspine B, induces apoptosis in melanoma cells by interfering with ceramide metabolism.
Marine environment has frequently afforded a variety of biologically active compounds with strong anticancer and cytotoxic properties. In the present study, the mechanism of action of Jaspine B, an anhydrophytosphingosine derivative isolated from the marine sponge Jaspis sp., was investigated. Jaspine B was able to dose- and time-dependently decrease the viability of murine B16 and human SK-Mel28 melanoma cells. On these cells, Jaspine B treatment triggered cell death by typical apoptosis as illustrated by phosphatidylserine externalization, the release of cytochrome c and caspase processing. These effects were associated with increased intracellular ceramide levels owing to perturbed ceramide metabolism. Indeed, Jaspine B exposure strongly inhibited the activity of sphingomyelin synthase (SMS), an enzyme that converts de novo ceramide into the membrane lipid sphingomyelin. Moreover, whereas Jaspine B-induced cell death was enhanced in SMS1-depleted cells, it was strongly inhibited in cells that stably overexpress human SMS1. Finally, the cytotoxic effects of Jaspine B truncated analogs were also shown to be dependent on SMS activity. Altogether, Jaspine B is able to kill melanoma cells by acting on SMS activity and consequently on ceramide formation, and may represent a new class of cytotoxic compounds with potential applications in anticancer melanoma therapy.
Institut National de la Santé et de la Recherche Médicale, Inserm U858, Toulouse, France.
Yahya
Y
Salma
Elodie
E
Lafont
Nicole
N
Therville
Stéphane
S
Carpentier
Marie-José
MJ
Bonnafé
Thierry
T
Levade
Yves
Y
Génisson
Nathalie
N
Andrieu-Abadie
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002518:Ceramides / Q000378:metabolism*; D002849:Chromatography, Gas; D006801:Humans; D008545:Melanoma / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D008856:Microscopy, Fluorescence; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D017855:Transferases (Other Substituted Phosphate Groups) / Q000037:antagonists & inhibitors
D002518:Ceramides; C468594:pachastrissamine; D017855:Transferases (Other Substituted Phosphate Groups); C070186:phosphatidylcholine-ceramide phosphocholine transferase; D013110:Sphingosine