title: De novo ceramide synthesis is responsible for the anti-tumor properties of camptothecin and doxorubicin in follicular thyroid carcinoma.
abstract: 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.
authors.affiliation: Université de Reims Champagne-Ardenne, Laboratoire SiRMa, CNRS UMR MEDyC 6237, Faculté des Sciences, Reims, France. geraldine.rath@uclouvain.be
authors.forename: Geraldine
authors.initials: G
authors.lastname: Rath
authors.forename: Christophe
authors.initials: C
authors.lastname: Schneider
authors.forename: Benoit
authors.initials: B
authors.lastname: Langlois
authors.forename: Hervé
authors.initials: H
authors.lastname: Sartelet
authors.forename: Hamid
authors.initials: H
authors.lastname: Morjani
authors.forename: Hassan E L
authors.initials: HE
authors.lastname: Btaouri
authors.forename: Stephane
authors.initials: S
authors.lastname: Dedieu
authors.forename: Laurent
authors.initials: L
authors.lastname: Martiny
mesh_terms: 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
chemical_list: D000903:Antibiotics, Antineoplastic; D000972:Antineoplastic Agents, Phytogenic; D002518:Ceramides; D004317:Doxorubicin; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; D002166:Camptothecin