RT Journal Article
SR Electronic
T1 Loss of Protein Kinase C<em>δ</em>/HuR Interaction Is Necessary to Doxorubicin Resistance in Breast Cancer Cell Lines
JF Journal of Pharmacology and Experimental Therapeutics
JO J Pharmacol Exp Ther
FD American Society for Pharmacology and Experimental Therapeutics
SP 99
OP 106
DO 10.1124/jpet.113.211839
VO 349
IS 1
A1 Elisa Latorre
A1 Ilaria Castiglioni
A1 Pamela Gatto
A1 Stephana Carelli
A1 Alessandro Quattrone
A1 Alessandro Provenzani
YR 2014
UL http://jpet.aspetjournals.org/content/349/1/99.abstract
AB The protein kinase Cδ (PKCδ) interacts with 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 serines 221 and 318 and cytoplasmic translocation. This series of events is crucial to elicit the death pathway triggered by doxorubicin and is necessary to promote HuR function in post-transcriptional regulation of gene expression, because genetic ablation of PKCδ caused the inability of HuR to bind its target mRNAs, topoisomerase IIα (TOP2A) included. In in vitro select 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 was 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.