title: Bortezomib-mediated expression of p27Kip1 through S-phase kinase protein 2 degradation in epithelial ovarian cancer.
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.
authors.affiliation: 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.
authors.forename: Shahab
authors.initials: S
authors.lastname: Uddin
authors.forename: Maqbool
authors.initials: M
authors.lastname: Ahmed
authors.forename: Azhar R
authors.initials: AR
authors.lastname: Hussain
authors.forename: Zeenath
authors.initials: Z
authors.lastname: Jehan
authors.forename: Fouad
authors.initials: F
authors.lastname: Al-Dayel
authors.forename: Adnan
authors.initials: A
authors.lastname: Munkarah
authors.forename: Prashant
authors.initials: P
authors.lastname: Bavi
authors.forename: Khawla S
authors.initials: KS
authors.lastname: Al-Kuraya
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D001897:Boronic Acids / Q000494:pharmacology / Q000627:therapeutic use*; D000069286:Bortezomib; D002277:Carcinoma / Q000188:drug therapy / Q000378:metabolism*; D020169:Caspases / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002945:Cisplatin / Q000627:therapeutic use; D050760:Cyclin-Dependent Kinase Inhibitor p27; D015536:Down-Regulation; D004789:Enzyme Activation / Q000187:drug effects; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects; D020411:Oligonucleotide Array Sequence Analysis; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology / Q000627:therapeutic use*; D044786:S-Phase Kinase-Associated Proteins / Q000378:metabolism*; D046888:Tissue Array Analysis; D014183:Transplantation, Heterologous; D015854:Up-Regulation
chemical_list: D000970:Antineoplastic Agents; D001897:Boronic Acids; C436291:CDKN1B protein, human; D047908:Intracellular Signaling Peptides and Proteins; D061988:Proteasome Inhibitors; D011719:Pyrazines; D044786:S-Phase Kinase-Associated Proteins; D050760:Cyclin-Dependent Kinase Inhibitor p27; D000069286:Bortezomib; D020169:Caspases; D002945:Cisplatin