The protein kinase C δ interacts and phosphorylates HuR, dictating its functionality. We show here that the genotoxic stimulus induced by doxorubicin triggers PKCδ interaction with HuR and leads to HuR phosphorylation on serine 221 and 318 and cytoplasmic translocation. This series of events is crucial to elicit the death pathway triggered by doxorubicin and is also necessary to promote HuR function in post-transcriptional regulation of gene expression, since genetic ablation of PKCδ brought to HuR inability to bind its target mRNAs, TOP2A included. In in vitro selected doxorubicin resistant human breast cancer cell lines upregulating the multidrug resistance marker ABCG2, PKCδ and HuR proteins were coordinately downregulated together with the doxorubicin target TOP2A protein, whose mRNA is HuR-regulated. Therefore, we show here that PKCδ, HuR and TOP2A constitute a network mediating doxorubicin efficacy in breast cancer cells. The importance of these molecular events in cancer therapy is suggested by their being profoundly suppressed in cells selected for doxorubicin resistance.
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