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 p27(Kip1). 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.