Eukaryotic Elongation Factor 2 Kinase (eEF2K) in Cancer

Abstract

Eukaryotic elongation factor 2 kinase (eEF2K) is a highly unusual protein kinase that negatively regulates the elongation step of protein synthesis. This step uses the vast majority of the large amount of energy and amino acids required for protein synthesis. eEF2K activity is controlled by an array of regulatory inputs, including inhibition by signalling through mammalian target of rapamycin complex 1 (mTORC1). eEF2K is activated under conditions of stress, such as energy depletion or nutrient deprivation, which can arise in poorly-vascularised tumours. In many such stress conditions, eEF2K exerts cytoprotective effects. A growing body of data indicates eEF2K aids the growth of solid tumours in vivo. Since eEF2K is not essential (in mice) under ‘normal’ conditions, eEF2K may be a useful target in the treatment of solid tumours. However, some reports suggest that eEF2K may actually impair tumorigenesis in some situations. Such a dual role of eEF2K in cancer would be analogous to the situation for other pathways involved in cell metabolism, such as autophagy and mTORC1. Further studies are needed to define the role of eEF2K in different tumour types and at differing stages in tumorigenesis, and to assess its utility as a therapeutic target in oncology.

Eukaryotic elongation factor 2 kinase promotes angiogenesis in hepatocellular carcinoma via PI3K/Akt and STAT3

“…S2 and S3). Taken together, in agreement with previous findings from other types of cancer cells, eEF2K aids HCC growth and progression.…”

“…Eukaryotic elongation factor 2 kinase (eEF2K), an atypical Ca 2+ /calmodulin‐dependent protein kinase, is a negative regulator of the elongation stage of mRNA translation, which phosphorylates and hence inactivates eEF2 . It is highly expressed in various metastatic tumors and is associated with poor prognosis in different types of human cancers . Several recent studies suggest that eEF2K plays an important role in promoting tumor cell migration and invasion .…”

“…It is highly expressed in various metastatic tumors and is associated with poor prognosis in different types of human cancers . Several recent studies suggest that eEF2K plays an important role in promoting tumor cell migration and invasion . siRNA‐mediated knockdown of eEF2K in A549 cells (human lung carcinoma) suppresses tumor development and metastasis .…”

Regulation of the Elongation Phase of Protein Synthesis Enhances Translation Accuracy and Modulates Lifespan

“…Consistent with this, when initiating ribosomes are stalled using harringtonine, TSC2 null cells (in which mTORC1 signaling is constitutively activated [15]) exhibit earlier ribosomal runoff, indicating a faster rate of translation elongation (reflecting disinhibition of eEF2), whereas rapamycin-which inhibits mTORC1-slows down elongation [11]. Conversely, eEF2K is activated by Ca 2+ ions at low pH and under various stress conditions [16].…”

“…As noted above, eEF2K is activated under diverse stress conditions [25][26][27][28][29]. Using A549 (human lung adenocarcinoma) cells, we first studied the effects of (1) energy deprivation, mimicked by treating cells with 2-deoxyglucose (2-DG), a glucose analog that can be phosphorylated by hexokinase but cannot be metabolized through glycolysis; consequently, it depletes cells of ATP; (2) nutrient deprivation (cells were transferred to Dulbecco's [D-] PBS); and (3) extracellular acidosis, which activates eEF2K [16]. We also treated cells (4) with the mTOR inhibitor AZD8055 [30], which alleviates inhibitory inputs into eEF2K (Figures S1K-S1S and S2A-S2D).…”