Abstract
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.
Highlights
HuR, 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
First we show that HuR undergoes cytoplasmic translocation in MCF-7 cells exposed to doxo, and that this translocation is necessary to the doxo-induced triggering of apoptosis
Doxorubicin induces HuR phosphorylation and nucleocytoplasmic shuttling Since HuR is induced to relocate from the nucleus to the cytoplasm following DNA damaging stimuli such as Ultraviolet radiation (UVR) [23], we reasoned that an anticancer agent known to induce DNA damage as doxorubicin could produce a similar effect
Summary
HuR, 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. Translational control is recognized as an increasingly important level of regulation of gene expression [10], but its impact in drug resistance has not yet been addressed fully. Among the major agents involved in translational control, the RNA binding protein (RBP) HuR is a pleiotropic protein [11] regulating many physiological processes. Many of the genes controlled by HuR are implicated in important physiological functions, such as embryonic development [14,15] and cell differentiation [16]. A caspase-truncated form of HuR has been identified as a promoter of cell death [21,22]
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