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Apoptosis and chemoresistance in human ovarian cancer: is Xiap a determinant?
1Department of Obstetrics and Gynaecology and Department of Cellular and Molecular Medicine, University of Ottawa, Loeb Health Research Institute, The Ottawa Hospital (Civic Campus), Canada.
Abstract:
Cisplatin-induced apoptosis in epithelial ovarian cancer cells is in part a consequence of suppressed Xiap expression and upregulation of the Fas/FasL system. Changes in the expression of these 'cell death' and 'cell survival' genes lead to activation of caspase-3, and cleavage of MDM2 and FAK. Failure of cancer cells to maintain a balance in the expression of these genes in favor of apoptotic cell death may be an important factor of chemoresistance. Xiap may be a novel target for gene therapy of human ovarian epithelial cancer and, dependent on P53 status, expression of Xiap antisense alone or in combination with wild-type P53 sense may offer a new approach for the treatment of the chemoresistant cancer.
Insights
Cisplatin chemotherapy triggers apoptosis in ovarian cancer by altering cell death and survival gene expression. Targeting Xiap (X-linked inhibitor of apoptosis protein) may overcome chemoresistance.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Cisplatin is a key chemotherapy agent for epithelial ovarian cancer (EOC).
- Chemoresistance remains a significant challenge in EOC treatment.
- The balance between cell death and cell survival genes influences treatment response.
Purpose of the Study:
- To investigate the molecular mechanisms underlying cisplatin-induced apoptosis in EOC cells.
- To identify key regulatory genes involved in chemoresistance.
- To explore Xiap as a potential therapeutic target for overcoming cisplatin resistance.
Main Methods:
- Analysis of gene expression changes in EOC cells treated with cisplatin.
- Focus on the roles of Xiap (X-linked inhibitor of apoptosis protein), Fas/FasL, caspase-3, MDM2, and FAK.
- Exploration of gene therapy strategies involving Xiap antisense and P53.
Main Results:
- Cisplatin treatment suppresses Xiap expression and upregulates the Fas/FasL system in EOC cells.
- These changes activate caspase-3 and lead to cleavage of MDM2 and FAK.
- Imbalance in these gene expressions favors chemoresistance.
Conclusions:
- Suppressed Xiap and activated Fas/FasL are crucial in cisplatin-induced apoptosis.
- Xiap dysregulation contributes to chemoresistance in EOC.
- Targeting Xiap, potentially with P53 modulation, offers a novel therapeutic strategy for chemoresistant ovarian cancer.