ZNF217 confers resistance to the pro-apoptotic signals of paclitaxel and aberrant expression of Aurora-A in breast cancer cells
| Autor: | Aurélie Thollet, Colin Collins, Julie A. Vendrell, Evelyne Grisard, Sabrina Ben Larbi, Marie Villedieu, Pascale A. Cohen, Sandra E. Ghayad, Léa Payen |
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| Rok vydání: | 2010 |
| Předmět: |
Cancer Research
Paclitaxel Blotting Western Mice Nude Breast Neoplasms Protein Serine-Threonine Kinases Biology lcsh:RC254-282 Mice chemistry.chemical_compound Aurora Kinases Cell Line Tumor Animals Humans Gene silencing RNA Small Interfering Aurora Kinase A Cell Proliferation Cyclin Regulation of gene expression Oncogene Reverse Transcriptase Polymerase Chain Reaction Cell growth Kinase Research Flow Cytometry lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Antineoplastic Agents Phytogenic Gene Expression Regulation Neoplastic Oncology chemistry Chromosomal region Trans-Activators Cancer research Molecular Medicine Female |
| Zdroj: | Molecular Cancer, Vol 9, Iss 1, p 291 (2010) Molecular Cancer |
| ISSN: | 1476-4598 |
| Popis: | Background ZNF217 is a candidate oncogene located at 20q13, a chromosomal region frequently amplified in breast cancers. The precise mechanisms involved in ZNF217 pro-survival function are currently unknown, and utmost importance is given to deciphering the role of ZNF217 in cancer therapy response. Results We provide evidence that stable overexpression of ZNF217 in MDA-MB-231 breast cancer cells conferred resistance to paclitaxel, stimulated cell proliferation in vitro associated with aberrant expression of several cyclins, and increased tumor growth in mouse xenograft models. Conversely, siRNA-mediated silencing of ZNF217 expression in MCF7 breast cancer cells, which possess high endogenous levels of ZNF217, led to decreased cell proliferation and increased sensitivity to paclitaxel. The paclitaxel resistance developed by ZNF217-overexpressing MDA-MB-231 cells was not mediated by the ABCB1/PgP transporter. However, ZNF217 was able to counteract the apoptotic signals mediated by paclitaxel as a consequence of alterations in the intrinsic apoptotic pathway through constitutive deregulation of the balance of Bcl-2 family proteins. Interestingly, ZNF217 expression levels were correlated with the oncogenic kinase Aurora-A expression levels, as ZNF217 overexpression led to increased expression of the Aurora-A protein, whereas ZNF217 silencing was associated with low Aurora-A expression levels. We showed that a potent Aurora-A kinase inhibitor was able to reverse paclitaxel resistance in the ZNF217-overexpressing cells. Conclusion Altogether, these data suggest that ZNF217 might play an important role in breast neoplastic progression and chemoresistance, and that Aurora-A might be involved in ZNF217-mediated effects. |
| Databáze: | OpenAIRE |
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