Absence of Bcl-xL down-regulation in response to cisplatin is associated with chemoresistance in ovarian carcinoma cells
| Autor: | F. Duigou, Pascal Gauduchon, E. Brotin, Laurent Poulain, Marie Villedieu, Cathy Staedel, S. Dutoit, Hubert Lincet, M.H. Louis |
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| Rok vydání: | 2006 |
| Předmět: |
bcl-X Protein
Down-Regulation Bcl-xL Antineoplastic Agents Apoptosis Biology Transfection Ovarian tumor Ovarian carcinoma Cell Line Tumor medicine Cytotoxic T cell Humans RNA Messenger Cisplatin Ovarian Neoplasms Dose-Response Relationship Drug Reverse Transcriptase Polymerase Chain Reaction Cell Cycle Obstetrics and Gynecology Cell cycle Molecular biology Oncology Drug Resistance Neoplasm biology.protein Female medicine.drug |
| Zdroj: | Gynecologic oncology. 105(1) |
| ISSN: | 0090-8258 |
| Popis: | Objective Recurrence and subsequent acquired chemoresistance to platinum-based treatments constitute major hurdles to ovarian carcinoma therapy. Our objective was to examine the involvement of Bcl-x L anti-apoptotic protein in resistance to cisplatin. Methods We described the effect of cisplatin on cell cycle and apoptosis induction in sensitive (IGROV1 and OAW42) and resistant (IGROV1-R10 and SKOV3) ovarian carcinoma cell lines. We correlated it with Bcl-x L mRNA and protein expression after exposure to cisplatin. We then used bcl - x S gene transfer to impede Bcl-x L activity. Results Our study showed that Bcl-x L basal expression was high in both sensitive and resistant cell lines, as well as in all the studied ovarian tumor samples. Thus, Bcl-x L basal expression could not allow to predict sensitivity. Wondering whether variation of Bcl-x L level in response to cisplatin could be a better determinant of sensitivity, we investigated the expression of this protein in the cell lines after treatment. Cisplatin-induced down-regulation of Bcl-x L was strictly associated with apoptosis and absence of recurrence in vitro. Conversely, the maintenance of Bcl-x L expression in response to cisplatin appeared as a sine qua non condition to escape to treatment. To try to sensitize SKOV3 cells by impeding anti-apoptotic activity of Bcl-x L , we transfected bcl-x S gene in these cells. Bcl-x S exogenous expression was only slightly cytotoxic on its own, but highly sensitized SKOV3 resistant cells to cisplatin-induced apoptosis, and delayed recurrence. Conclusion This work thus provides one more argument to put Bcl-x L forward as a pertinent target of inhibition to overcome chemoresistance of epithelial ovarian carcinoma. |
| Databáze: | OpenAIRE |
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