Cancer Research Landon Prizes for Basic and Translational Cancer Research Tumor Immunology: New Perspectives
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
This Article
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Fraser, M.
Right arrow Articles by Tsang, B. K.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Fraser, M.
Right arrow Articles by Tsang, B. K.
[Cancer Research 63, 7081-7088, November 1, 2003]
© 2003 American Association for Cancer Research

Advances in Brief

p53 Is a Determinant of X-Linked Inhibitor of Apoptosis Protein/Akt-Mediated Chemoresistance in Human Ovarian Cancer Cells1

Michael Fraser2, Brendan M. Leung2, Xiaojuan Yan, Han C. Dan, Jin Q. Cheng and Benjamin K. Tsang3

Reproductive Biology Unit and Division of Gynaecological Oncology, Departments of Obstetrics and Gynaecology and Cellular and Molecular Medicine, University of Ottawa, Ottawa Health Research Institute, The Ottawa Hospital (Civic Campus), Ottawa, KIY 4E9 Canada [M. F., B. M. L., X. Y., B. K. T.], and Department of Pathology, University of South Florida College of Medicine and H. Lee Moffitt Cancer Center, Tampa, Florida 33612 [H. C. D., J. Q. C.]

We established previously that X-linked inhibitor of apoptosis protein (Xiap) is a determinant of cisplatin (CDDP) resistance in human ovarian cancer cells and that down-regulation of Xiap sensitizes cells to CDDP in the presence of wild-type p53. Furthermore, Xiap up-regulates the phosphatidylinositol 3'-kinase/Akt pathway by increasing Akt phosphorylation. However, the precise relationships among Xiap, Akt, and p53 in chemoresistance are unknown. Here we show that both Xiap and Akt can modulate CDDP sensitivity individually but that Xiap requires Akt for its full function. Furthermore, dominant-negative Akt sensitizes ovarian cancer cells to CDDP (10 µM), an effect that is absent in cells expressing mutant p53 or treated with the p53 inhibitor pifithrin-{alpha}-hydrobromide (30 µM) but restored by exogenous wild-type p53. CDDP increased p53, decreased Xiap content, and induced apoptosis in OV2008 cells but not in the resistant counterpart (C13*). However, dominant-negative Akt restored all of these characteristics to C13* cells. Expression of a constitutively active Akt2 prevented CDDP-mediated down-regulation of Xiap and apoptosis in A2780s cells. Akt2-mediated chemoresistance could not be reversed by Xiap down-regulation. These results suggest that whereas Xiap, Akt2, and p53 are important mediators of chemoresistance in ovarian cancer cells, Akt2 may be an important regulator of both Xiap and p53 contents after CDDP challenge. Inhibition of Xiap and/or Akt expression/function may be an effective means of overcoming chemoresistance in ovarian cancer cells expressing either endogenous or reconstituted wild-type p53.




This article has been cited by other articles:


Home page
 Cancer Res.Home page
M. R. Abedini, E. J. Muller, J. Brun, R. Bergeron, D. A. Gray, and B. K. Tsang
Cisplatin Induces p53-Dependent FLICE-Like Inhibitory Protein Ubiquitination in Ovarian Cancer Cells
Cancer Res., June 15, 2008; 68(12): 4511 - 4517.
[Abstract] [Full Text] [PDF]

Home page
 J. Cell Sci.Home page
A. Astanehe, D. Arenillas, W. W. Wasserman, P. C. K. Leung, S. E. Dunn, B. R. Davies, G. B. Mills, and N. Auersperg
Mechanisms underlying p53 regulation of PIK3CA transcription in ovarian surface epithelium and in ovarian cancer
J. Cell Sci., March 1, 2008; 121(5): 664 - 674.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
A. A. Goyeneche, R. W. Caron, and C. M. Telleria
Mifepristone Inhibits Ovarian Cancer Cell Growth In vitro and In vivo
Clin. Cancer Res., June 1, 2007; 13(11): 3370 - 3379.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
Y. Zhang and X. Shen
Heat Shock Protein 27 Protects L929 Cells from Cisplatin-Induced Apoptosis by Enhancing Akt Activation and Abating Suppression of Thioredoxin Reductase Activity
Clin. Cancer Res., May 15, 2007; 13(10): 2855 - 2864.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
D. Sohn, F. Essmann, K. Schulze-Osthoff, and R. U. Janicke
p21 Blocks Irradiation-Induced Apoptosis Downstream of Mitochondria by Inhibition of Cyclin-Dependent Kinase-Mediated Caspase-9 Activation
Cancer Res., December 1, 2006; 66(23): 11254 - 11262.
[Abstract] [Full Text] [PDF]

Home page
 Mol. Endocrinol.Home page
H. Wang, J.-Y. Jiang, C. Zhu, C. Peng, and B. K. Tsang
Role and Regulation of Nodal/Activin Receptor-Like Kinase 7 Signaling Pathway in the Control of Ovarian Follicular Atresia
Mol. Endocrinol., October 1, 2006; 20(10): 2469 - 2482.
[Abstract] [Full Text] [PDF]

Home page
 Cancer Res.Home page
X. Yang, M. Fraser, U. M. Moll, A. Basak, and B. K. Tsang
Akt-Mediated Cisplatin Resistance in Ovarian Cancer: Modulation of p53 Action on Caspase-Dependent Mitochondrial Death Pathway.
Cancer Res., March 15, 2006; 66(6): 3126 - 3136.
[Abstract] [Full Text] [PDF]

Home page
 Reproductive SciencesHome page
A. B. Alvero, W. Chen, A. C. Sartorelli, P. Schwartz, T. Rutherford, and G. Mor
Triapine (3-aninopyridine-2-carboxaldehyde thiosemicarbazone) Induces Apoptosis in Ovarian Cancer Cells
Reproductive Sciences, February 1, 2006; 13(2): 145 - 152.
[Abstract] [PDF]

Home page
 Ann. N. Y. Acad. Sci.Home page
E. C. LACASSE, E. R. KANDIMALLA, P. WINOCOUR, T. SULLIVAN, S. AGRAWAL, J. W. GILLARD, and J. DURKIN
Application of XIAP Antisense to Cancer and Other Proliferative Disorders: Development of AEG35156/ GEM(R)640
Ann. N.Y. Acad. Sci., November 1, 2005; 1058(1): 215 - 234.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
S. Gery, D. Xie, D. Yin, H. Gabra, C. Miller, H. Wang, D. Scott, W. S. Yi, M. L. Popoviciu, J. W. Said, et al.
Ovarian Carcinomas: CCN Genes Are Aberrantly Expressed and CCN1 Promotes Proliferation of these Cells
Clin. Cancer Res., October 15, 2005; 11(20): 7243 - 7254.
[Abstract] [Full Text] [PDF]

Home page
 Clin. Cancer Res.Home page
A. Okamoto, T. Nikaido, K. Ochiai, S. Takakura, M. Saito, Y. Aoki, N. Ishii, N. Yanaihara, K. Yamada, O. Takikawa, et al.
Indoleamine 2,3-Dioxygenase Serves as a Marker of Poor Prognosis in Gene Expression Profiles of Serous Ovarian Cancer Cells
Clin. Cancer Res., August 15, 2005; 11(16): 6030 - 6039.
[Abstract] [Full Text] [PDF]

Home page
 J. Biol. Chem.Home page
Q. Liu, S. Kaneko, L. Yang, R. I. Feldman, S. V. Nicosia, J. Chen, and J. Q. Cheng
Aurora-A Abrogation of p53 DNA Binding and Transactivation Activity by Phosphorylation of Serine 215
J. Biol. Chem., December 10, 2004; 279(50): 52175 - 52182.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
G. Xu, Y. Zhong, S. Munir, B. B. Yang, B. K. Tsang, and C. Peng
Nodal Induces Apoptosis and Inhibits Proliferation in Human Epithelial Ovarian Cancer Cells via Activin Receptor-Like Kinase 7
J. Clin. Endocrinol. Metab., November 1, 2004; 89(11): 5523 - 5534.
[Abstract] [Full Text] [PDF]


HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Cancer Research Clinical Cancer Research
Cancer Epidemiology Biomarkers & Prevention Molecular Cancer Therapeutics
Molecular Cancer Research Cancer Prevention Research
Cancer Prevention Journals Portal Cancer Reviews Online
Annual Meeting Education Book Meeting Abstracts Online
Copyright © 2003 by the American Association for Cancer Research.