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Bortezomib-mediated expression of p27Kip1 through S-phase kinase protein 2 degradation in epithelial ovarian cancer. 2009

Shahab Uddin, and Maqbool Ahmed, and Azhar R Hussain, and Zeenath Jehan, and Fouad Al-Dayel, and Adnan Munkarah, and Prashant Bavi, and Khawla S Al-Kuraya
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.

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.

UI MeSH Term Description Entries
D008819 Mice, Nude Mutant mice homozygous for the recessive gene "nude" which fail to develop a thymus. They are useful in tumor studies and studies on immune responses. Athymic Mice,Mice, Athymic,Nude Mice,Mouse, Athymic,Mouse, Nude,Athymic Mouse,Nude Mouse
D008928 Mitochondria Semiautonomous, self-reproducing organelles that occur in the cytoplasm of all cells of most, but not all, eukaryotes. Each mitochondrion is surrounded by a double limiting membrane. The inner membrane is highly invaginated, and its projections are called cristae. Mitochondria are the sites of the reactions of oxidative phosphorylation, which result in the formation of ATP. They contain distinctive RIBOSOMES, transfer RNAs (RNA, TRANSFER); AMINO ACYL T RNA SYNTHETASES; and elongation and termination factors. Mitochondria depend upon genes within the nucleus of the cells in which they reside for many essential messenger RNAs (RNA, MESSENGER). Mitochondria are believed to have arisen from aerobic bacteria that established a symbiotic relationship with primitive protoeukaryotes. (King & Stansfield, A Dictionary of Genetics, 4th ed) Mitochondrial Contraction,Mitochondrion,Contraction, Mitochondrial,Contractions, Mitochondrial,Mitochondrial Contractions
D010051 Ovarian Neoplasms Tumors or cancer of the OVARY. These neoplasms can be benign or malignant. They are classified according to the tissue of origin, such as the surface EPITHELIUM, the stromal endocrine cells, and the totipotent GERM CELLS. Cancer of Ovary,Ovarian Cancer,Cancer of the Ovary,Neoplasms, Ovarian,Ovary Cancer,Ovary Neoplasms,Cancer, Ovarian,Cancer, Ovary,Cancers, Ovarian,Cancers, Ovary,Neoplasm, Ovarian,Neoplasm, Ovary,Neoplasms, Ovary,Ovarian Cancers,Ovarian Neoplasm,Ovary Cancers,Ovary Neoplasm
D011719 Pyrazines A heterocyclic aromatic organic compound with the chemical formula C4H4N2. Pyrazine
D001897 Boronic Acids Inorganic or organic compounds that contain the basic structure RB(OH)2. Boronic Acid,Acid, Boronic,Acids, Boronic
D002277 Carcinoma A malignant neoplasm made up of epithelial cells tending to infiltrate the surrounding tissues and give rise to metastases. It is a histological type of neoplasm and not a synonym for "cancer." Carcinoma, Anaplastic,Carcinoma, Spindle-Cell,Carcinoma, Undifferentiated,Carcinomatosis,Epithelial Neoplasms, Malignant,Epithelioma,Epithelial Tumors, Malignant,Malignant Epithelial Neoplasms,Neoplasms, Malignant Epithelial,Anaplastic Carcinoma,Anaplastic Carcinomas,Carcinoma, Spindle Cell,Carcinomas,Carcinomatoses,Epithelial Neoplasm, Malignant,Epithelial Tumor, Malignant,Epitheliomas,Malignant Epithelial Neoplasm,Malignant Epithelial Tumor,Malignant Epithelial Tumors,Neoplasm, Malignant Epithelial,Spindle-Cell Carcinoma,Spindle-Cell Carcinomas,Tumor, Malignant Epithelial,Undifferentiated Carcinoma,Undifferentiated Carcinomas
D002453 Cell Cycle The complex series of phenomena, occurring between the end of one CELL DIVISION and the end of the next, by which cellular material is duplicated and then divided between two daughter cells. The cell cycle includes INTERPHASE, which includes G0 PHASE; G1 PHASE; S PHASE; and G2 PHASE, and CELL DIVISION PHASE. Cell Division Cycle,Cell Cycles,Cell Division Cycles,Cycle, Cell,Cycle, Cell Division,Cycles, Cell,Cycles, Cell Division,Division Cycle, Cell,Division Cycles, Cell
D002945 Cisplatin An inorganic and water-soluble platinum complex. After undergoing hydrolysis, it reacts with DNA to produce both intra and interstrand crosslinks. These crosslinks appear to impair replication and transcription of DNA. The cytotoxicity of cisplatin correlates with cellular arrest in the G2 phase of the cell cycle. Platinum Diamminodichloride,cis-Diamminedichloroplatinum(II),cis-Dichlorodiammineplatinum(II),Biocisplatinum,Dichlorodiammineplatinum,NSC-119875,Platidiam,Platino,Platinol,cis-Diamminedichloroplatinum,cis-Platinum,Diamminodichloride, Platinum,cis Diamminedichloroplatinum,cis Platinum
D004789 Enzyme Activation Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1, activation by ions (activators); 2, activation by cofactors (coenzymes); and 3, conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme. Activation, Enzyme,Activations, Enzyme,Enzyme Activations
D005260 Female Females

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