Abstract
Abstract We have previously shown that the function of Ycf1p, yeast ortholog of MRP1, is regulated by yeast casein kinase 2α (Cka1p) via phosphorylation at Ser251. In this study we explore whether CK2α, the human homolog of Cka1p, regulates MRP1 by phosphorylation at the semi-conserved site, Thr249. Knockdown of CK2α in MCF7-derived cells expressing MRP1 (MRP1 CK2β(−)) resulted in increased doxorubicin sensitivity. MRP1-dependent transport of LTC4 and E217αG into vesicles derived from MRP1 CK2β(−) cells was decreased compared with MRP1 vesicles. Moreover, Thr249 to alanine mutation (MRP1-T249A) also resulted in decreased MRP1-dependent transport, while a phosphomimicking mutation (MRP1-T249E) led to dramatic increase in MRP1-dependent transport. Studies in tissue culture confirmed these findings showing increased intracellular doxorubicin accumulation in MRP1 CK2β(−) and MRP1-T249A cells compared to MRP1 cells. Inhibition of CK2 kinase by DMAT resulted in increased doxorubicin accumulation in MRP1 cells, but not in MRP1 CK2β(−), MRP1-T249A or MRP1-T249E cells, suggesting that CK2α regulates MRP1 function via phosphorylation of Thr249. Indeed, CK2α and MRP1 interact physically and recombinant CK2 phosphorylates MRP1 derived peptide in vitro in Thr249 dependent manner, while knockdown of CK2α results in decreased phosphorylation at MRP1-T249. The role of CK2 in regulating MRP1 was confirmed in other cancer cell lines where CK2 inhibition decreased MRP1-mediated efflux of doxorubicin. This study supports a model in which CK2α potentiates MRP1 function via direct phosphorylation of Thr249. We believe that addition of CK2 inhibitors to cancer treatments will improve therapeutic outcome in part due to reversal of MRP1- mediated drug resistance. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 788. doi:1538-7445.AM2012-788
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