title: Role of JNK/ATF-2 pathway in inhibition of thrombospondin-1 (TSP-1) expression and apoptosis mediated by doxorubicin and camptothecin in FTC-133 cells.
abstract: Our previous studies have shown that camptothecin and doxorubicin triggered ceramide accumulation via de novo synthesis pathway. De novo ceramide generation was responsible for the drug-induced apoptosis through a caspase-3-dependent pathway and a decrease of thrombospondin-1 expression in human thyroid carcinoma FTC-133 cells. Here, we demonstrate that Jun N-terminal kinases play a critical role in camptothecin- and doxorubicin-induced down-regulation of thrombospondin-1 expression: i) de novo ceramide synthesis pathway activates Jun N-terminal kinase 1/2 resulting in activating transcription factor 2 phosphorylation; ii) cell treatment by SP600125, a Jun N-terminal kinase specific inhibitor, strongly reduced activating transcription factor 2 phosphorylation and completely abolished camptothecin and doxorubicin effects; and iii) activating transcription factor 2 expression silencing greatly attenuated camptothecin- and doxorubicin-induced down-regulation of thrombospondin-1 expression and apoptosis. The set of our data established that camptothecin- and doxorubicin-induced activation of Jun N-terminal kinase/activating transcription factor 2 pathway via de novo ceramide synthesis down-regulates thrombospondin-1 expression and apoptosis in human thyroid carcinoma FTC-133 cells. This article is part of a Special Issue entitled: 11th European Symposium on Calcium.
authors.affiliation: Laboratoire SiRMa (Signalisation Cellulaire et Récepteurs Matriciels), UMR-CNRS 6237, UFR Sciences, Reims, France. Hassan.elbtaouri@univ-reims.fr
authors.forename: Hassan
authors.initials: H
authors.lastname: El Btaouri
authors.forename: Hamid
authors.initials: H
authors.lastname: Morjani
authors.forename: Yannick
authors.initials: Y
authors.lastname: Greffe
authors.forename: Emmanuelle
authors.initials: E
authors.lastname: Charpentier
authors.forename: Laurent
authors.initials: L
authors.lastname: Martiny
mesh_terms: D051698:Activating Transcription Factor 2 / Q000378:metabolism*; D000873:Anthracenes / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D002166:Camptothecin / Q000494:pharmacology*; D053148:Caspase 3 / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects*; D013110:Sphingosine / Q000031:analogs & derivatives / Q000494:pharmacology; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000201:enzymology / Q000235:genetics / Q000473:pathology
chemical_list: C497105:ATF2 protein, human; D051698:Activating Transcription Factor 2; D000873:Anthracenes; C064769:N-acetylsphingosine; D019700:Thrombospondin 1; C432165:pyrazolanthrone; D004317:Doxorubicin; D048031:JNK Mitogen-Activated Protein Kinases; D053148:Caspase 3; D013110:Sphingosine; D002166:Camptothecin