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Altered Expression of c-IAP1, Survivin, and Smac Contributes to Chemotherapy Resistance in Thyroid Cancer Cells

¹ Department of Biomedical Sciences, Section of General Pathology and ² Department of Internal and Specialistic Medicine, Section of Endocrinology, University of Catania; ³ Department of Experimental Oncology, Istituto Oncologico del Mediterraneo, Catania; and ⁴ Department of Surgical and Oncological Sciences, University of Palermo, Palermo, Italy

Requests for reprints: Paolo Vigneri, Department of Biomedical Sciences, Section of General Pathology, University of Catania, Via Androne 83, 95124 Catania, Italy. Phone: 39-95-312389; Fax: 39-95-715-1928; E-mail: pvigneri{at}libero.it.

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. (Cancer Res 2006; 66(8): 4263-72)

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