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

We 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.The 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.Insurgence of drug resistance during chemotherapy is a major cause of cancer relapse and consequent failure of therapy for cancer patients. Genetic and epigenetic changes, resulting in gene expression reprogramming, play a major role in allowing adaptation to the presence of anticancer drugs [1]. One of the most important aspects of this phenomenon is the development of resistance and cross resistance to drugs having a mechanism of action unrelated to the single chemotherapeutic agent originally causing resistance, i.e. the MultiDrug Resistance phenotype (MDR) [2]. Resistance mechanisms are extremely complex, changing according to the type of drug that was used in therapy and spanning from the overexpression of drug extrusion pumps, as in the case of seve