Tirrò Elena, Consoli Maria Letizia, Massimino Michele, Manzella Livia, Frasca Francesco, Sciacca Laura, Vicari Luisa, Stassi Giorgio, Messina Luigi, Messina Angelo, Vigneri Paolo
Department of Biomedical Sciences, Section of General Pathology, University of Catania, Italy.
Cancer Res. 2006 Apr 15;66(8):4263-72. doi: 10.1158/0008-5472.CAN-05-3248.
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.
对化疗的耐药性预示着放射性碘不敏感型甲状腺癌患者的预后不良。为了探究这种耐药性背后的机制，我们评估了四种不同凋亡抑制蛋白及其拮抗剂Smac在经顺铂、阿霉素或紫杉醇处理48小时后仍存活的甲状腺癌细胞中的表达情况。我们发现顺铂处理后c-IAP1水平升高，阿霉素处理后survivin表达增加。经受紫杉醇处理的细胞显示Smac表达降低，且从线粒体释放的该蛋白量极少。下调c-IAP1和survivin可增加顺铂和阿霉素的细胞毒性，而Smac的过表达则提高了紫杉醇的疗效。最后，对阿霉素或顺铂永久耐药的甲状腺癌细胞分别显示c-IAP1和survivin表达增加。然而，通过RNA干扰使这些蛋白沉默可恢复对阿霉素和顺铂的敏感性。因此，在甲状腺癌细胞中，对化疗药物的早期耐药需要高水平的c-IAP1和survivin以及低水平的Smac。此外，c-IAP1和survivin表达的增加有助于获得对细胞毒性化合物的永久耐药性。
