Abstract
Eukaryotic elongation factor 2 kinase (eEF-2K), through its phosphorylation of elongation factor 2 (eEF2), provides a mechanism by which cells can control the rate of the elongation phase of protein synthesis. The activity of eEF-2K is increased in rapidly proliferating malignant cells, is inhibited during mitosis, and may contribute to the promotion of autophagy in response to anti-cancer therapies. The purpose of this study was to examine the therapeutic potential of targeting eEF-2K in breast cancer tumors. Through the systemic administration of liposomal eEF-2K siRNA (twice a week, i.v. 150 µg/kg), the expression of eEF-2K was down-regulated in vivo in an orthotopic xenograft mouse model of a highly aggressive triple negative MDA-MB-231 tumor. This targeting resulted in a substantial decrease in eEF2 phosphorylation in the tumors, and led to the inhibition of tumor growth, the induction of apoptosis and the sensitization of tumors to the chemotherapy agent doxorubicin. eEF-2K down-modulation in vitro resulted in a decrease in the expression of c-Myc and cyclin D1 with a concomitant increase in the expression of p27Kip1. A decrease in the basal activity of c-Src (phospho-Tyr-416), focal adhesion kinase (phospho-Tyr-397), and Akt (phospho-Ser-473) was also detected following eEF-2K down-regulation in MDA-MB-231 cells, as determined by Western blotting. Where tested, similar results were seen in ER-positive MCF-7 cells. These effects were also accompanied by a decrease in the observed invasive phenotype of the MDA-MB-231 cells. These data support the notion that the disruption of eEF-2K expression in breast cancer cells results in the down-regulation of signaling pathways affecting growth, survival and resistance and has potential as a therapeutic approach for the treatment of breast cancer.
Highlights
Breast Cancer is the most common malignancy in women in the Western world
Studies using the non-specific compound rottlerin suggested that eukaryotic elongation factor 2 kinase (eEF-2K) is important for the proliferation of breast cancer cells [11]
We examined the growth-sensitivity of the two breast cancer cell lines MDA-MB-231 and MCF-7 to the depletion of eEF-2K
Summary
Breast Cancer is the most common malignancy in women in the Western world. Every year about 200, 000 women are diagnosed with breast cancer in the US, and more than 40,000 die from this disease. EEF-2K is an unusual calcium/calmodulin (Ca2+/CaM)-dependent Ser/Thr-kinase that is subject to extensive regulation by posttranslational phosphorylation [4,5]. In recent years eukaryotic elongation factor 2 kinase (eEF-2K) has garnered interest as a potential cancer-therapeutic target [3]. It phosphorylates elongation factor 2 (eEF2), an event associated with decreased global protein translation [6]. A recent assessment of eEF-2K by siRNA-mediated knockdown as well as by a moderately potent ATP-competitive inhibitor of eEF-2K suggested that the contribution of eEF-2K to the proliferation of several common cancer cell lines is minimal [13]. A comparison of the rate of proliferation of fibroblasts between wild type fibroblasts and those derived from mice lacking eEF-2K has not been reported
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