De novo ceramide synthesis is responsible for the anti-tumor properties of camptothecin and doxorubicin in follicular thyroid carcinoma.
Doxorubicin and camptothecin are two cytotoxic chemotherapeutic agents triggering apoptosis in various cancer cells, including thyroid carcinoma cells. Recent studies revealed a critical role of ceramide in chemotherapy and suggested that anti-cancer drugs may kill tumor cells through sphingomyelinase activation. However, in comparison to sphingomyelin hydrolysis, the relative involvement of de novo ceramide synthesis remained poorly explored and highly controversial. Here, we evidenced that both doxorubicin and camptothecin triggered ceramide accumulation in thyroid carcinoma cells. We demonstrated that ceramide increase occurred via the de novo pathway without neither acidic nor neutral sphingomyelinase contribution. Interestingly, de novo ceramide generation was responsible for the drug-induced malignant cell apoptosis through a caspase-3-dependent pathway and a decrease of thrombospondin amount. Furthermore, blocking ceramide metabolism by inhibiting glucosylceramide synthase strengthened the camptothecin and doxorubicin-dependent effects. Altogether, we evidenced that de novo ceramide synthesis mediates the anti-tumor properties of doxorubicin and camptothecin in thyroid carcinoma and suggested that glucosylation of ceramide may contribute to the drug-resistance phenotype in thyroid malignancies.
Rath
Geraldine
G
Université de Reims Champagne-Ardenne, Laboratoire SiRMa, CNRS UMR MEDyC 6237, Faculté des Sciences, Reims, France. geraldine.rath@uclouvain.be
Schneider
Christophe
C
Langlois
Benoit
B
Sartelet
Hervé
H
Morjani
Hamid
H
Btaouri
Hassan E L
HE
Dedieu
Stephane
S
Martiny
Laurent
L
D018263:Adenocarcinoma, Follicular / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002518:Ceramides / Q000096:biosynthesis*; D004317:Doxorubicin / Q000494:pharmacology*; D006801:Humans; D010088:Oxidoreductases / Q000378:metabolism; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D002518:Ceramides; D004317:Doxorubicin; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; D002166:Camptothecin