1. ¹Department 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
2. ²Department of Pathology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
3. ³Department of Gynecology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia

Correspondence: Dr KS Al-Kuraya, MD, FCAP, Department of Human Cancer Genomic Research, King Fahad National Centre for Children's Cancer and Research, King Faisal Specialist Hospital and Research Centre, MBC 98-16, PO Box 3354, Riyadh 11211, Saudi Arabia. E-mail: kkuraya@kfshrc.edu.sa

⁴These authors contributed equally to this work.

Received 24 March 2009; Revised 3 June 2009; Accepted 4 June 2009; Published online 27 July 2009.

Abstract

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.