Abstract
Abstract S-phase kinase protein 2 (SKP2), an F-box protein, targets cell cycle regulators including cycle-dependent kinase inhibitor p27Kip1 via ubiquitin-mediated degradation. SKP2 is frequently overexpressed in a variety of cancers. In this study, we investigated the role of SKP2 and its ubiquitin-proteasome pathway in Papillary Thyroid Cancer (PTC) in a panel of PTC cell lines, a large cohort PTC patient samples and NUDE mouse model using tissue microarray, MTT, flow cytometry and DNA fragmentation assays and western blotting. Our data showed that bortezomib caused a dose-dependent growth inhibition in all cell lines studied. The IC 50 was 83.7nM and 61.4nM for B-CPAP1 and TPC-1 respectively. Cell cycle assay showed that the sub-G1 population of B-CPAP1 cell increased from 4.09% in untreated control sample to 36.74% after 25nM treatment for 2 days and 71.91% after 50nM treatment for 2 days. Further confirmation using FITC-conjugated Annexin V and PI assay showed that apoptotic cell increased form 8.43% in untreated cells to 47.6% and 64.82% after 25nM and 50nM treatment respectively in B-CPAP1 cells and from 12.72% in control to 48.16% and 64.02% in TPC-1 cells, indicating a dose-dependent apoptosis induced in both cell lines. Treatment of PTC cell line cells with bortezomib or expression of small interfering RNA of SKP2 caused down-regulation of SKP2 and accumulation of p27Kip1. Furthermore, treatment of PTC cells with bortezomib caused apoptosis by involving the mitochondrial pathway and activation of caspases-9 and 3, and cleavage PARP. Pretreatment with zVAD-fmk abrogated bortezomib induced apoptosis. In addition, treatment of PTC cells with bortezomib down-regulated the expression of XIAP, cIAP1, and survivin. Currently the animal study and data analysis of patient samples are still ongoing. Our preliminary results suggest that SKP2 and the ubiquitin-proteasome pathway may be potential targets for therapeutic intervention for treatment of TPC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1016. doi:10.1158/1538-7445.AM2011-1016
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