Dexamethasone inhibits TRAIL-induced apoptosis of thyroid cancer cells via Bcl-xL induction.
We have investigated the effect of dexamethasone (DEX) on the apoptosis induced by TRAIL (tumour necrosis factor-related apoptosis inducing ligand) in follicular undifferentiated thyroid (FRO) cancer cells. Apoptosis was measured by percent hypodiploid nuclei, caspase-3 and -8 activation, and mitochondrial membrane depolarisation. DEX nearly abolished TRAIL-induced apoptosis. The DEX protective effect was reverted by the steroid receptor antagonist RU486 suggesting that the DEX action is mediated by glucocorticoid receptor (GR) activation. The role of Bcl proteins in the DEX effect was then investigated. In FRO cells DEX stimulated in a time-dependent fashion the expression of Bcl-xL, but not that of Bcl-2, Bax and Bad. In addition, Bcl-xL mRNA was significantly increased in the presence of DEX, suggesting a transcriptional regulation by the steroid. Transfection of the cells with siRNAs against Bcl-xL inhibited both basal and DEX-stimulated Bcl-xL expression and restored apoptosis in TRAIL-stimulated cells treated with DEX. These results demonstrate that dexamethasone protects thyroid cancer cells from apoptosis induced by TRAIL. DEX acts via GR activation and up-regulation of the expression of the anti-apoptotic protein Bcl-xL.
Petrella
Antonello
A
Department of Pharmaceutical Sciences, University of Salerno, Via Ponte Don Melillo, 84084 Fisciano, Salerno, Italy.
Ercolino
Simona Francesca
SF
Festa
Michela
M
Gentilella
Antonio
A
Tosco
Alessandra
A
Conzen
Suzanne D
SD
Parente
Luca
L
D018931:Antineoplastic Agents, Hormonal / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D018265:Carcinoma, Papillary, Follicular / Q000188:drug therapy*; D003907:Dexamethasone / Q000627:therapeutic use*; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000037:antagonists & inhibitors*; D013964:Thyroid Neoplasms / Q000188:drug therapy*; D014407:Tumor Cells, Cultured; D051020:bcl-X Protein / Q000378:metabolism*
D018931:Antineoplastic Agents, Hormonal; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D053221:TNF-Related Apoptosis-Inducing Ligand; D051020:bcl-X Protein; D003907:Dexamethasone