Uddin Shahab, Ahmed Maqbool, Hussain Azhar R, Jehan Zeenath, Al-Dayel Fouad, Munkarah Adnan, Bavi Prashant, Al-Kuraya Khawla S
Department of Human Cancer Genomic Research, King Fahad National Centre for Children's Cancer and Research, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
Lab Invest. 2009 Oct;89(10):1115-27. doi: 10.1038/labinvest.2009.75. Epub 2009 Jul 27.
S-phase kinase protein 2 (SKP2), an F-box protein, targets cell-cycle regulators including cyclin-dependent kinase inhibitor p27Kip1 through ubiquitin-mediated degradation. SKP2 is frequently overexpressed in variety of cancers. We investigated the function of SKP2 and its ubiquitin-proteasome pathway in a large series (156) of epithelial ovarian cancer (EOC) patient samples, using a panel of cell lines, and nude mouse model. Using immunohistochemistry, we detected SKP2 in 13.2% tumor samples and found that it was inversely associated with p27Kip1. EOC subset with high level of SKP2 and low level of p27Kip1 showed a strong association with proliferative marker Ki167 (P<0.0014). Treatment of EOC cell lines with bortezomib or expression of siRNA of SKP2 causes downregulation of SKP2 and accumulation of p27Kip1. In addition, co-treatment of EOC with bortezomib and cisplatin causes more pronounced effect on cell proliferation, apoptosis and downregulation of SKP2 leading to accumulation of p27kip1. Bortezomib treatment of EOC cells causes apoptosis by involving mitochondrial pathway, activation of caspases and downregulation of XIAP, and survivin. Finally, treatment of EOC cell line xenografts with bortezomib resulted in growth inhibition of tumors in nude mice through downregulation of SKP2 and accumulation of p27Kip1. Altogether, our results suggest that SKP2 and ubiquitin-proteasome pathway may be a potential target for therapeutic intervention for treatment of EOC.
S期激酶相关蛋白2（SKP2）是一种F-box蛋白，通过泛素介导的降解作用靶向细胞周期调节因子，包括细胞周期蛋白依赖性激酶抑制剂p27Kip1。SKP2在多种癌症中经常过度表达。我们使用一组细胞系和裸鼠模型，在大量（156例）上皮性卵巢癌（EOC）患者样本中研究了SKP2及其泛素-蛋白酶体途径的功能。通过免疫组织化学，我们在13.2%的肿瘤样本中检测到SKP2，并发现它与p27Kip1呈负相关。SKP2水平高而p27Kip1水平低的EOC亚组与增殖标志物Ki67密切相关（P<0.0014）。用硼替佐米处理EOC细胞系或表达SKP2的小干扰RNA会导致SKP2下调和p27Kip1积累。此外，硼替佐米和顺铂联合处理EOC对细胞增殖、凋亡以及SKP2下调导致p27kip1积累有更显著的影响。硼替佐米处理EOC细胞通过线粒体途径、半胱天冬酶激活以及XIAP和生存素下调诱导凋亡。最后，用硼替佐米处理EOC细胞系异种移植物导致裸鼠肿瘤生长受抑制，这是通过下调SKP2和积累p27Kip1实现的。总之，我们的结果表明SKP2和泛素-蛋白酶体途径可能是EOC治疗性干预的潜在靶点。
