ZNF217 confers resistance to the pro-apoptotic signals of paclitaxel and aberrant expression of Aurora-A in breast cancer cells

Molecular Cancer

Research

Colin Collins¹  Sabrina Ben Larbi²  Marie Villedieu³  Aurélie Thollet³  Sandra E Ghayad³  Léa Payen³  Julie A Vendrell³  Pascale A Cohen³  Evelyne Grisard³ 

[1] Departement of urology, Vancouver Prostate Centre, Vancouver, Canada;Université de Lyon, Lyon, France;ISPB, Faculté de Pharmacie de Lyon, Université Lyon 1, Lyon, France;Université de Lyon, Lyon, France;ISPB, Faculté de Pharmacie de Lyon, Université Lyon 1, Lyon, France;INSERM, U590, Lyon, France;Centre Léon Bérard, FNCLCC, Lyon, France;

关键词: Breast Cancer Cell;    Paclitaxel;    MCF7 Cell;    Paclitaxel Resistance;    Aurora Kinase Inhibitor;   

DOI  :  10.1186/1476-4598-9-291

 received in 2010-04-10, accepted in 2010-11-08,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundZNF217 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.ResultsWe 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.ConclusionAltogether, 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.

【 授权许可】

Unknown   
© Thollet et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.