Downregulation of HuR as a new mechanism of doxorubicin resistance in breast cancer cells

Molecular Cancer

Research

Alessandro Provenzani¹  Elisa Latorre¹  Antonino Maria Spartಠ Toma Tebaldi²  Alessandro Quattrone²  Gabriella Viero³ 

[1] Laboratory of Genomic Screening, Centre for Integrative Biology, CIBIO, University of Trento, Trento, Italy;Laboratory of Translational Genomics, Centre for Integrative Biology, CIBIO, University of Trento, Trento, Italy;Laboratory of Translational Genomics, Centre for Integrative Biology, CIBIO, University of Trento, Trento, Italy;CNR Institute of Biophysics, Povo, Trento, Italy;

关键词: HuR;    Doxorubicin;    Drug resistance;    Apoptosis;    Translational regulation;   

DOI  :  10.1186/1476-4598-11-13

 received in 2011-10-19, accepted in 2012-03-21,  发布年份 2012

来源: Springer

【 摘 要 】

BackgroundHuR, an RNA binding protein involved in the post-transcriptional regulation of a wide spectrum of mRNAs, has been demonstrated to be a determinant of carcinogenesis and tumor aggressiveness in several cancer types. In this study, we investigated the role of HuR in the apoptosis and in the chemoresistance induced by the widely used anticancer drug doxorubicin in human breast cancer cells (MCF-7).ResultsWe showed that HuR acts in the early phase of cell response to doxorubicin, being induced to translocate into the cytoplasm upon phosphorylation. Reducing HuR levels diminished the apoptotic response to doxorubicin. Doxorubicin-induced apoptosis was also correlated with the presence of HuR in the cytoplasm. Rottlerin, which was able to block HuR nuclear export, had correspondingly antagonistic effects with doxorubicin on cell toxicity. The proapoptotic activity of HuR was not due to cleavage to an active form, as was previously reported. In in vitro selected doxorubicin resistant MCF-7 cells (MCF-7/doxoR) overexpressing the multidrug resistance (MDR) related ABCG2 transporter, we observed a significant HuR downregulation that was paralleled by a corresponding downregulation of HuR targets and by loss of rottlerin toxicity. Restoration of HuR expression in these cells resensitized MCF-7/doxoR cells to doxorubicin, reactivating the apoptotic response.ConclusionsThe present study shows that HuR is necessary to elicit the apoptotic cell response to doxorubicin and that restoration of HuR expression in resistant cells resensitizes them to the action of this drug, thereby identifying HuR as a key protein in doxorubicin pharmacology.

【 授权许可】

Unknown   
© Latorre et al; licensee BioMed Central Ltd. 2012. 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.