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Biochemistry and Biophysics |
Reproductive Biology Unit and Division of Gynaecologic Oncology, Departments of Obstetrics and Gynaecology and Cellular and Molecular Medicine, University of Ottawa, and Loeb Health Research Institute, The Ottawa Hospital, Civic Campus, Ottawa, Ontario, Canada K1Y 4E9 [H. S., Y. S., B. K. T]; and Department of Obstetrics and Gynaecology, Fukui Medical University, Fukui, Japan 910-1193 [F. K.]
Cisplatin-centeredchemotherapy is a key treatment for ovarian cancer, but resistance to chemotherapeutic agents remains a major cause of treatment failure. Multiple factors are known to contribute to the development of this chemoresistance. Although it has been demonstrated that X-linked inhibitor of apoptosis protein (Xiap) prevents apoptosis by inhibiting effector caspases, if and how it is important in chemoresistance in ovarian cancer has not been studied. The effects of Xiap down-regulation and/or restoration of wild type p53 by recombinant adenovirus infection were examined on four ovarian epithelial cancer cell lines [C13*, A2780-s (wild type p53), A2780-cp (mutant p53), and SKOV3 (null p53)]. Apoptosis and protein expression (e.g., Xiap, caspase-3, p53, MDM2, and p21waf1) were assessed by Hoechst 33258 stain and Western blot, respectively. We demonstrated that Xiap down-regulation following adenoviral antisense expression induces apoptosis in the wild-type p53 cells, but not in the mutated or null cells. Xiap down-regulation resulted in caspase-3 activation, caspase-mediated MDM2 processing, and p53 accumulation. Restoration of wild type p53 in the p53-mutated or -null cells significantly enhanced the proapoptotic effect of Xiap antisense expression. Down-regulation of Xiap induced apoptosis in chemoresistant ovarian cancer cells, a process dependent on p53 status.
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F. Guo, R. Nimmanapalli, S. Paranawithana, S. Wittman, D. Griffin, P. Bali, E. O'Bryan, C. Fumero, H. G. Wang, and K. Bhalla Ectopic overexpression of second mitochondria-derived activator of caspases (Smac/DIABLO) or cotreatment with N-terminus of Smac/DIABLO peptide potentiates epothilone B derivative-(BMS 247550) and Apo-2L/TRAIL-induced apoptosis Blood, May 1, 2002; 99(9): 3419 - 3426. [Abstract] [Full Text] [PDF]
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 Y. Deng, Y. Lin, and X. Wu TRAIL-induced apoptosis requires Bax-dependent mitochondrial release of Smac/DIABLO Genes & Dev., January 1, 2002; 16(1): 33 - 45. [Abstract] [Full Text] [PDF]
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A. Gruslin, Q. Qiu, and B. K. Tsang Influence of Maternal Smoking on Trophoblast Apoptosis Throughout Development: Possible Involvement of Xiap Regulation Biol Reprod, October 1, 2001; 65(4): 1164 - 1169. [Abstract] [Full Text] [PDF]
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 G. K. Yiu, W. Y. Chan, S.-W. Ng, P. S. Chan, K. K. Cheung, R. S. Berkowitz, and S. C. Mok SPARC (Secreted Protein Acidic and Rich in Cysteine) Induces Apoptosis in Ovarian Cancer Cells Am. J. Pathol., August 1, 2001; 159(2): 609 - 622. [Abstract] [Full Text]
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C. G. Ferreira, P. van der Valk, S. W. Span, I. Ludwig, E. F. Smit, F. A. E. Kruyt, H. M. Pinedo, H. van Tinteren, and G. Giaccone Expression of X-linked Inhibitor of Apoptosis as a Novel Prognostic Marker in Radically Resected Non-Small Cell Lung Cancer Patients Clin. Cancer Res., August 1, 2001; 7(8): 2468 - 2474. [Abstract] [Full Text] [PDF]
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E. Asselin, G. B. Mills, and B. K. Tsang XIAP Regulates Akt Activity and Caspase-3-dependent Cleavage during Cisplatin-induced Apoptosis in Human Ovarian Epithelial Cancer Cells Cancer Res., March 1, 2001; 61(5): 1862 - 1868. [Abstract] [Full Text]
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C. W. Xiao, K. Ash, and B. K. Tsang Nuclear Factor-{{kappa}}B-Mediated X-Linked Inhibitor of Apoptosis Protein Expression Prevents Rat Granulosa Cells from Tumor Necrosis Factor {{alpha}}-Induced Apoptosis Endocrinology, February 1, 2001; 142(2): 557 - 563. [Abstract] [Full Text] [PDF]
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J. Li, Q. Feng, J.-M. Kim, D. Schneiderman, P. Liston, M. Li, B. Vanderhyden, W. Faught, M. F. K. Fung, M. Senterman, et al. Human Ovarian Cancer and Cisplatin Resistance: Possible Role of Inhibitor of Apoptosis Proteins Endocrinology, January 1, 2001; 142(1): 370 - 380. [Abstract] [Full Text] [PDF]
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