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Review article

Roles of eEF-2 kinase in cancer

LIU, Xiao-yuan; ZHANG, Li; ZHANG, Yi; YANG, Jin-ming

Editor(s): WANG, De

Author Information
doi: 10.3760/cma.j.issn.0366-6999.2012.16.020
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Abstract

Eukaryotic elongation factor 2 kinase (eEF-2 kinase) activity is found in virtually all mammalian tissues as well as in various invertebrate organisms. eEF-2 kinase is also known as Ca2+/calmodulin-dependent protein kinase and was first identified by Nairn et al.1 The level of eEF-2 kinase activity changes with such processes as oogenesis, cellular differentiation and malignant transformation. It is a structurally and functionally unique protein kinase which is overexpressed in several types of cancer cell lines and human malignancies, and has been shown to regulate many cellular processes through its essential role in controlling protein translation.2

Cloning and sequencing of eEF-2 kinase revealed unique characteristics.3 The ability to phosphorylate serine and threonine residues within alpha helices and a catalytic domain with sequence homology to bacterial histidine kinases. The phosphorylation at multiple (such as Thr56, Ser366, Ser78 and Ser398) sites can regulate the activity of eEF-2 kinase. Our current understanding of the structural domains of eEF-2 kinase is that the amino terminus contains both the CaM binding domain (aa 51-96) and the catalytic domain of the kinase, while the carboxyl terminus contains the eEF-2 targeting domain. A unique region that recognizes eEF-2 and presents the substrate to the catalytic domain is contained within the amino terminus lobe.4

eEF-2 kinase phosphorylates and inactivates eukaryotic elongation factor-2 at two threonine residues that are conserved in all eukaryotes. eEF-2 is a 100 kDa protein, a key mediator of ribosomal transfer and protein translation that promotes ribosomal translocation and the reaction that induces movement of mRNA along the ribosome during translation in eukaryotic tissues.5 As the sole factor responsible for the translocation of codons from the A to P ribosomal positions, upon eEF-2 inactivation via phosphorylation or ADP ribosylation, protein synthesis is halted with mRNA-loaded ribosomes primed to resume protein synthesis once it is freed from the inactivating influence.6 As the only known substrate of eEF-2 kinase, the inactivation of eEF-2 is achieved via phosphorylation on Thr56 by this dedicated kinase. Phosphorylation of eEF-2 can decrease the affinity for and preclude functional binding to the ribosome, thereby stalling the elongation of nascent proteins.7 That is, eEF-2 kinase regulates peptide elongation.

The eEF-2/eEF-2 kinase pathway is a key biochemical sensor, which is a link between external signals and protein synthesis.5 Phosphorylation of eEF-2 by eEF-2 kinase results in the inactivation of eEF-2. Because eEF-2 kinase is Ca2+ and calmodulin dependent, eEF-2 phosphorylation is a mechanism by which changes of the intracellular calcium concentration can modulate the rate of protein synthesis.2 In other words, eEF-2 kinase and eEF-2 have an inverse relationship in as much as when one enzyme is more active, the other is necessarily more inactive. For example, growth factors and nutrients result in inhibition of eEF-2 kinase, that allows eEF-2 activation and then allows translation to proceed. In contrast, starvation, hypoxia and oxidative stress stimulate eEF-2 kinase, which phosphorylates and inactivates eEF-2 thereby interrupting protein translation.8

However, the precise role of this kinase in malignancy is not fully understood. This review will provide a concise summary of the relationship between the eEF-2/eEF-2 kinase pathway and each phase of malignant cancer. It is certainly an important relationship, in that eEF-2 kinase influences tumor progression, and the specific importance of this relationship for understanding and treating cancer will also be discussed.

EEF-2 KINASE AND TUMORS ONCOGENESIS

Cancer arises from a loss of normal growth control. In normal tissues, the rates of new cell growth and old cell death are kept in balance. In cancer, this balance is disrupted. The differences in activity of CaM kinases between normal and malignant tissues might elucidate the roles of these enzymes in cell proliferation. However, in terms of the eEF-2 kinase, the precise role of this kinase in cell proliferation is not fully understood.

ABERRANT EXPRESSION OF EEF-2 KINASE IN HUMAN CANCERS

eEF-2 kinase is up-regulated in many human cancers, such as malignant glioma and breast cancer.9,10 Connolly et al11 demonstrated that the protein expression level of eEF-2 kinase in non-transformed cells is kept low by proteasome degradation. In contrast, as cells transform to highly malignant cells, the expression level of eEF-2 kinase increases. These results are consistent with our original reports demonstrating that eEF-2 kinase is regulated by ubiquitin-mediated proteasome degradation,12 and that eEF-2 kinase is constitutively up-regulated in cancer cell lines and tumor specimens,10,13 and that inhibiting this kinase results in a decreased viability of tumor cells.14 The overexpression of eEF-2 kinase seen in cancer suggests that this protein fills critical niches in the life of a cancer cell. This observation makes it a potential target for cancer therapeitics.

EEF-2 KINASE AND THE PROTEIN SYNTHESIS

Protein synthesis is a finely tuned and tightly controlled process. In particular, the elongation stage of protein synthesis, controlled by eEF-2 and eEF-2 kinase, may offer clues to the origins and perpetuation of cancer cells; an important subject which has attracted the attention of many cancer researchers. There is a significant amount of experimental data offering clear evidence for the existence of regulatory mechanisms at this stage.5 In contrast to many other phosphorylation events of proteins involved in translation, phosphorylation of eEF-2 has a strong effect on its activity. Phosphorylated eEF-2 is unable to catalyze ribosome translocation, and it is inactive in a poly(U)-directed cell-free translation system.2 In addition, phosphorylation of eEF-2 can also affect translation of mature mRNA.

On the other hand, maintaining protein synthesis in a metabolically disordered cell is one of the most complicated challenges that cancer cells face.8 In fact, protein synthesis is dysregulated in development and growth of cancers. In addition, anti-apoptotic proteins are not uncommon in cancers, and tumor cells have a general propensity to express higher levels of them. For instance, the upregulation of survivin levels in cancer cells has been widely observed. Anti-apoptotic proteins generally have short half-lives. One consequence of this is that interruption of protein synthesis can quickly result in cellular caspases losing their opposition.15

Cancer cells may be at risk for the dysregulation because they experience a high level of metabolic stress due to their characteristic metabolic insatiability. Thus, it seems likely that adaptive cancer cells require a mechanism to absorb the influences which phosphorylate eEF-2, inhibit protein synthesis, and potentially leave the cell with too few anti-apoptotic proteins.8 One potential solution is the upregulation of eEF-2 itself to ensure maintenance of basal enzymatic activity in a stressful environment. Because this protein is a key component of the translational machinery and the key mediator of ribosomal transfer and protein translation, conserving its function is critical to tumor cell survival.

EEF-2 KINASE AND THE CELL CYCLE

Preserving an active cell cycle is a key physiological task for cancer cells that is closely related to protein synthesis, another key physiological function. Research has shown that eEF-2 and eEF-2 kinase may be overexpressed in cancer cells in part to modulate their influence over the cell cycle.8 We present here a model for how the elongation phase of protein synthesis, governed by eEF-2 and eEF-2 kinase, both modulates and responds in the cell cycle. Furthermore, interestingly for cancer researchers, eEF-2 and eEF-2 kinase also follow a prescribed pattern during the progression of the cell cycle.8 A summary of cellular protein synthesis at each stage of the cell cycle, the mechanisms that govern this activity and the consequences of the loss of regulation, follows. During the G1-phase (protein synthesis) of the cell cycle, protein synthesis is enabled, requiring eEF-2 activity. Due to the reciprocal relationship of eEF-2 and eEF-2 kinase, this phase requires the inactivation of eEF-2 kinase. In this phase, eEF-2 kinase is inactivated by phosphorylation of Ser366, and forcing the activation of eEF-2 kinase results in G1 arrest.

The entry into S phase (DNA synthesis) requires the activation of eEF-2 kinase. In this phase, eEF-2 kinase is activated by the rise in cAMP and Cap2 levels, and the inhibition of eEF-2 kinase precludes entry into S phase. During G2/M phases (proofreading and cell division), the cellular pool of eEF-2 is phosphorylated by eEF-2 kinase and protein synthesis drops precipitously.16 In this phase, eEF-2 is inactivated by phosphorylation at Thr56 and forced activation of eEF-2 results in G2/M arrest. The mechanism of protein elongation is closely tied to progression through the cell cycle, such that loss of regulation of the eEF-2/eEF-2 kinase pathway in tumor cells can alter the cell cycle.

EEF-2 KINASE AND TUMORS PROGRESSION

The typical history of the natural growth of malignant tumors can be divided into several stages; the malignant transformation of cells into a cell clone, their hyperplasia, local invasion and dissemination with infiltration of distant metastasis. In this process, the inherent characteristics of malignant transformation of cells (such as the loss of cell cycle control, the abrogation of contact inhibition and anchorage dependence17) and the response of the host to the tumor cells or their products (e.g. tumor angiogenesis and establishment of the tumor microenvironment17) together allow cancer cells to survive, proliferate, and disseminate. The sum of these activities affects the tumor growth and evolution.

EEF-2 KINASE AND TUMOR ANGIOGENESIS

Like normal tissues, tumors require sustenance in the form of nutrients and oxygen as well as an ability to evacuate metabolic wastes and carbon dioxide. The tumor-associated neovasculature, generated by the process of angiogenesis, addresses these needs.17 Some studies suggest that angiogenesis is induced surprisingly early during the multistage development of invasive cancers. This is seen both in animal models and in human tumors.18 During tumor progression, angiogenesis is almost always activated and it remains on, causing normally quiescent vasculature to continually sprout new vessels that help sustain expanding neoplastic growth.19

Khan et al20 demonstrated that resveratrol can inhibit the proliferation and migration of vascular endothelial cells by activating eEF-2 kinase, which in turn phosphorylates and inactivates eEF-2 through the the eEF-2/eEF-2 kinase pathway. In addition, functional inhibition of the kinase by gene deletion in vivo or by RNAi, as well as pharmacological inhibition in vitro, is able to completely reverse the effects of resveratrol on blood vessel growth. These studies have uncovered a novel and critical pathway by which resveratrol regulates angiogenesis.

Abnormal angiogenesis is central to the pathophysiology of diverse disease processes including ischemic and atherosclerotic heart disease, as well as cancers.20 And resveratrol can inhibit abnormal angiogenesis by inhibiting eEF-2 activity via eEF-2 kinase to ameliorate and decelerate the aging process as well as blunt end organ damage from obesity. Hence, tumor-associated neovasculature may be regulated through the eEF-2/eEF-2 kinase pathway.

EEF-2 KINASE AND TUMOR INVASION AND METASTASIS

Malignant tumors are tumors that are capable of spreading by invasion and metastasis, which involve the spread of tumor cells from a primary tumor site into normal tissues. Local invasion refers to the direct migration and penetration by cancer cells into neighboring tissues. Distant metastasis refers to the ability of cancer cells to penetrate into lymphatics and blood vessels, circulate through the bloodstream or lymph, and invade normal tissues elsewhere in the body. These processes involve the coordination of several signal-transduction pathways that allow cancer cells to proliferate, remodel their surrounding environment, invade distant sites, and establish new tumors.21 Our group studied the invasive potential of tumor cells using a matrigel chamber assay and the migrating capabilities in a wound-healing assay of glioma cells with or without silencing of eEF-2 kinase expression. The results suggest that the invasiveness is significantly decreased and wound healing is greatly inhibited when eEF-2 kinase is knocked down compared with control cells. Other results from our group suggest the silencing of eEF-2 kinase expression can enhance sensitivity to anoikis and expression of eEF-2 kinase confers resistance to anoikis, which is a hallmark of migrating and invasive glioma cells.22 In a word, the expression of this kinase plays an important role in the invasion and migration of glioma cells. Because eEF-2 kinase appears to promote both tumor-associated invasion and metastasis, these steps can be regulated through the eEF-2/eEF-2 kinase pathway.

EEF-2 KINASE AND TUMOR CELLS SURVIVAL

Resisting cell death is one of the hallmarks of cancer and is comprised of six biological capabilities.17 The ability to survive in harsh conditions is an essential trait of cancer cells. One suggested mechanism of resisting cell death is the widely observed upregulation of survivin levels in cancer cells.23 Autophagy, apoptosis and necrosis have previously been described as distinct static processes that induce and execute cell death. However, a growing body of knowledge disputes the view that the cell death process is merely one static “suicide” pathway a cell commits to, but rather argues that it is the net result of a dynamic integrative signaling network, which permits molecular overlap and grey zones.24 In many conditions, cell death may still manifest as a distinct morphology of one of the above types, including autophagy, apoptosis and necrosis.25

ROLE OF EEF-2 KINASE IN AUTOPHAGY

Autophagy is a highly conserved cellular process for large-scale degradation of proteins and organelles.26 This process has been implicated in several pathologies, including cancer and neuro-degeneration. Autophagy is a double-edged sword, although it may be activated in cell death, evidence suggests that in most cases, and especially in cancer, it is not a contributing factor.27 Instead, the literature suggests that autophagy plays a fundamental role in the cell's survival mechanisms.25,28

Several results from our work suggest that eEF-2 kinase may be involved in autophagy. First, eEF-2 kinase regulates protein synthesis, a major consumer of cellular energy. Second, eEF-2 kinase lies downstream of mTOR, a known negative regulator of autophagy. Third, growth factor deprivation can markedly reduce the activity of eEF-2 kinase.29 Yet, a role for eEF-2 kinase in autophagy has not been unequivocally identified.

Therefore, our group has studied the role of eEF-2 kinase in autophagy. Knockdown of eEF-2 kinase by RNA interference inhibited autophagy in several cell types.29 In contrast, overexpression of eEF-2 kinase increased autophagy. Furthermore, inhibition of autophagy markedly decreased the viability of glioblastoma cells grown under conditions of nutrient depletion.30 These results suggest that eEF-2 kinase plays a regulatory role in the autophagy process in glioma cells and may promote cancer cell survival under conditions of nutrient deprivation through regulating autophagy. eEF-2 kinase activity is markedly increased in most cancer types, including glioblastoma, and inhibition of eEF-2 kinase promotes rapid cancer cell death. Therefore, eEF-2 kinase plays a regulatory role in the autophagy process in tumor cells and increased activity of eEF-2 kinase may be a part of self-sufficient growth mechanism of cancer cells.

ROLE OF EEF-2 KINASE IN APOPTOSIS AND NECROSIS

Apoptosis has come to be used synonymously with the phrase “programmed cell death”, as it is an intrinsic cell mechanism for suicide, which is regulated by a variety of cellular signaling pathways.31 Autophagy can also function as a second mode of PCD (Type II PCD) that is distinct from apoptosis.32 Finely tuned interplay exists between apoptosis and autophagy.33 Studies have suggested that there is crosstalk between the autophagy and apoptosis pathways. These two pathways are regulated by certain common factors and share common components, each of which may regulate and modify the activity of the other.34 In fact, under certain circumstances, inhibition of autophagy can trigger apoptosis, and upregulation of autophagy protects against the onset of apoptosis.35 The inverse relationship between autophagy and the onset of apoptosis is likely to be manifest when decreasing or inhibiting autophagy.24

Molecular links between apoptosis and autophagy have also been reported to be important in determining cell survival or death.36 Akt is a key downstream effector of the PI3K signaling pathway that regulates cell survival and proliferation. Our recent study demonstrated that inhibition of eEF-2 kinase can suppress autophagy but it promotes apoptosis in tumor cells subjected to Akt inhibition. This indicates a role for eEF-2 kinase as a controller in the cross-talk between autophagy and apoptosis.37 Another recent study also showed a molecular link between autophagy and necrosis. It is suggested that necrosis manifests as a result of an unsuccessful autophagic stress response,38 which supports our view that autophagy is induced as a stress response to increase the likelihood of survival. Similarly, tumor cells with combined defects in apoptosis and autophagy are prone to necrosis in response to metabolic stress.

Therefore, when autophagy and apoptosis are both inhibited, necrotic cell death may induced. However, the underlying mechanisms that dictate the functional relationship between autophagy and necrosis, or between apoptosis and necrosis, that are regulated through the eEF-2/eEF-2 kinase pathway remain to be elucidated.

EEF-2 KINASE AND TUMORS THERAPY

Cancer development requires the acquisition of several capabilities that include increased replicative potential, angiogenesis, invasion of surrounding tissues and metastasis, and evasion of apoptosis. eEF-2 kinase has emerged as promoting many of these phenotypes when deregulated. It appears that the findings of increased levels of eEF-2 kinase in various cancers, and the inhibition of its expression and activity being anti-tumorigenic, make eEF-2 kinase an attractive target for cancer therapeutics.

It appears that eEF-2 kinase has applications in the area of cancer therapies, and it has also been found that the eEF-2/eEF-2 kinase pathway plays a part in the mechanism of action of some long-used drugs. For example, Taxol, which is one of the oldest and most used members of the chemotherapeutic arsenal, is widely considered to act by stabilizing microtubules and thereby arresting cycling cells in the G2/M phase.39 It was recently observed that, exposure to Taxol resulted in the persistent phosphorylation of eEF-2 by an unknown mechanism. Whether the eEF-2 phosphorylation is a contributing cause of arrest in G2/M or a result of the arrest is still an open question.40 Another commonly used drug to consider is Doxorubicin. Upon treatment, doxorubicin interacts with intracellular iron and the subsequent generation of free radicals. eEF-2 is then strongly phosphorylated, protein translation is halted, cells arrest in G2/M, and stores of short half-life proteins with anti-apoptotic functions are quickly depleted. This leaves cells more susceptible to induction of cell death.15 Since most chemotherapy agents generate free radicals, that can potentially result in the phosphorylation of eEF-2, the physiological shifts induced when protein synthesis is halted may be an under-studied contributor to any number of drug effects.41

Several drugs which inhibit eEF-2 kinase activity including rottlerin, geldanamycin,42 and the imidazolium histidine kinase inhibitor-NH125,14 have shown that, without activation of eEF-2 kinase, the cell cycle arrests at S phase, resulting in the inhibition of DNA synthesis and eventual death of the cell. Thus, treating eEF-2 kinase as an explicit target may be a reasonable strategy. Currently, only NH125 has demonstrable specificity for eEF-2 kinase.14

Recently, our findings also suggested that targeting eEF-2 kinase may reinforce the antitumor efficacy of Akt inhibitors, such is MK-2206.37 In that study, we investigated regulatory mechanisms through which apoptosis and autophagy were modulated in tumor cells subjected to Akt inhibition by MK-2206. Suppression of MK-2206 induced autophagy by eEF-2 silencing was accompanied by the promotion of apoptotic cell death. Similarly, siRNA-mediated inhibition of eEF-2 kinase potentiated the efficacy of MK-2206 against glioma cells. Together, these results showed that blunting autophagy and augmenting apoptosis by inhibition of eEF-2 kinase could modulate the sensitivity of glioma cells to Akt inhibition.43 Another study proposed a new treatment strategies that it may be based on a combined therapy, targeting autophagic as well as apoptotic pathways.44 Considering the relationship between the eEF-2 and eEF-2 kinase pathway in tumors, we can gain a new idea as to how eEF-2 kinase inhibitors may increase the effect of oncology drugs when used together to treatment malignant tumors.

CONCLUDING REMARKS AND FUTURE PROSPECTS

This review relates the observation that the overexpression of eEF-2 kinase is seen in cancer, and suggests that this protein fills a critical niche in the life of a cancer cell. It highlights that the increased activity of eEF-2 kinase in cancer cells is a protective mechanism to allow tumor growth and evolution, to resist cell death through the eEF-2/eEF-2 kinase pathway, and to make cells potential targets for tumor therapy.

We can test our central hypothesis that the activity of eEF-2 kinase promotes survival of stressed cancer cells through activating autophagy and delaying apoptosis, thereby contributing to the malignant phenotypes such as invasion and migration, and resistance to treatments. We predict that inhibiting eEF-2 kinase will blunt autophagy, decrease malignant tumor resilience, and hasten cell death via apoptosis. The data gleaned from these studies may be critically important to developing new approaches to effective treatments for cancer patients. The overall significance of these studies lies in their potential to improve survival and life quality of patients with malignant tumors.

The proposed studies are supported by our extensive experience in studying eEF-2 kinase and our expertise in molecular biology, pharmacology and cancer biology. We have already identified NH125 as a novel, selective and potent inhibitor of eEF-2 kinase,14 and this relatively specific inhibitor of eEF-2 kinase has significant activity against several human cancer cell lines. Future studies should be designed to determine the antitumor activity of this inhibitor in vivo to define whether inhibitors of eEF-2 kinase are good candidates for future development as cancer therapeutic agents.

We should further study eEF-2 kinase inhibitors, like NH125, as either a drug or a synergistic therapeutic agent for cancer therapy. And the proposed studies of the combined use of eEF-2 kinase inhibitors with chemotherapy, radiotherapy or other treatments for patients with some intractable and lethal tumors will also have potential clinical value.

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Keywords:

elongation factor 2 kinase; neoplastic; tumors progression; tumor cells survival; tumors therapy

© 2012 Chinese Medical Association