Altered expression of c-IAP1, survivin, and Smac contributes to chemotherapy resistance in thyroid cancer cells.
Resistance to chemotherapy predicts an unfavorable outcome for patients with radioiodine-insensitive thyroid cancer. To investigate the mechanisms underlying this resistance, we evaluated the expression of four different inhibitor of apoptosis proteins, and their antagonist, Smac, in thyroid cancer cells that survived 48 hours of exposure to cisplatin, doxorubicin, or taxol. We found high levels of c-IAP1 after cisplatin treatment and increased expression of survivin following exposure to doxorubicin. Cells that endured treatment with taxol showed reduced expression of Smac and released minimal amounts of this protein from the mitochondria. Down-regulation of c-IAP1 and survivin increased the cytotoxicity of cisplatin and doxorubicin, whereas overexpression of Smac improved the efficacy of taxol. Finally, thyroid cancer cells permanently resistant to doxorubicin or cisplatin showed increased expression of c-IAP1 and survivin, respectively. However, silencing of these proteins by RNA interference restored sensitivity to doxorubicin and cisplatin. Thus, in thyroid cancer cells, early resistance to chemotherapeutic agents requires high levels of c-IAP1 and survivin and low levels of Smac. Furthermore, increased expression of c-IAP1 and survivin contributes to the acquisition of permanent resistance to cytotoxic compounds.
Tirrò
Elena
E
Department of Biomedical Sciences, Section of General Pathology, University of Catania, Italy.
Consoli
Maria Letizia
ML
Massimino
Michele
M
Manzella
Livia
L
Frasca
Francesco
F
Sciacca
Laura
L
Vicari
Luisa
L
Stassi
Giorgio
G
Messina
Luigi
L
Messina
Angelo
A
Vigneri
Paolo
P
D000970:Antineoplastic Agents / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple / Q000502:physiology*; D019008:Drug Resistance, Neoplasm; D006801:Humans; D051034:Inhibitor of Apoptosis Proteins / Q000096:biosynthesis*; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins / Q000096:biosynthesis*; D024101:Mitochondrial Proteins / Q000096:biosynthesis*; D009363:Neoplasm Proteins / Q000096:biosynthesis*; D017239:Paclitaxel / Q000494:pharmacology; D000077022:Survivin; D013964:Thyroid Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D051636:X-Linked Inhibitor of Apoptosis Protein / Q000096:biosynthesis
D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C107489:BIRC5 protein, human; C412403:DIABLO protein, human; D051034:Inhibitor of Apoptosis Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D009363:Neoplasm Proteins; D000077022:Survivin; D051636:X-Linked Inhibitor of Apoptosis Protein; C496866:XIAP protein, human; D004317:Doxorubicin; D017239:Paclitaxel; D002945:Cisplatin