The C-terminal CD47/IAP-binding domain of thrombospondin-1 prevents camptothecin- and doxorubicin-induced apoptosis in human thyroid carcinoma cells.
Camptothecin and doxorubicin belong to a family of anticancer drugs that exert cytotoxic effects by triggering apoptosis in various cell types. However there have only been few investigations showing that matricellular proteins like thrombospondin-1 (TSP-1) could be involved in the underlying mechanism of this cytotoxicity. In this report, using Hoechst reagent staining, reactive oxygen species production and caspase-3 activity measurement, we determined that both camptothecin and doxorubicin induced apoptosis in human thyroid carcinoma cells (FTC-133). On the one hand, we demonstrated that camptothecin and doxorubicin inhibited TSP-1 expression mainly occurring at the transcriptional level. On the other hand, drug-induced apoptosis determined by western blot analysis for PARP cleavage and caspase-3 activity measurement, was significantly decreased in presence of exogenous TSP-1. In order to identify the sequence responsible for this effect, we used the CD47/IAP-binding peptide 4N1 (RFYVVMWK), derived from the C-terminal domain of TSP-1, and known to play a role in apoptosis. Thus, in presence of 4N1, camptothecin and doxorubicin-induced pro-apoptotic activity was considerably inhibited. These findings suggest that induction of apoptosis by camptothecin or doxorubicin in FTC-133 cells is greatly dependent by a down-regulation of TSP-1 expression and shed new light on a possible role for TSP-1 in drug resistance.
Rath
G M
GM
Université de Reims Champagne-Ardenne, IFR 53 Biomolécules, UMR-CNRS 6198 Matrice extracellulaire et régulation cellulaire, UFR Sciences de Reims, Moulin de la Housse-BP 1039-51687 Reims Cedex 2, France. geraldine.rath@univ-reims.fr
Schneider
C
C
Dedieu
S
S
Rothhut
B
B
Soula-Rothhut
M
M
Ghoneim
C
C
Sid
B
B
Morjani
H
H
El Btaouri
H
H
Martiny
L
L
D017209:Apoptosis; D001665:Binding Sites; D051928:CD47 Antigen / Q000235:genetics / Q000378:metabolism*; D002166:Camptothecin / Q000494:pharmacology*; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D004317:Doxorubicin / Q000494:pharmacology*; D006801:Humans; D019700:Thrombospondin 1 / Q000235:genetics / Q000378:metabolism*; D013964:Thyroid Neoplasms / Q000378:metabolism* / Q000473:pathology; D013997:Time Factors; D014162:Transfection
D051928:CD47 Antigen; D019700:Thrombospondin 1; D004317:Doxorubicin; D002166:Camptothecin