Elongation factor 2 in cancer: a promising therapeutic target in protein translation

Abstract

Aberrant elongation of proteins can lead to the activation of oncogenic signaling pathways, resulting in the dysregulation of oncogenic signaling pathways. Eukaryotic elongation factor 2 (eEF2) is an essential regulator of protein synthesis that precisely elongates nascent peptides in the protein elongation process. Although studies have linked aberrant eEF2 expression to various cancers, research has primarily focused on its structure, highlighting a need for deeper exploration into its molecular functions. In this review, recent advancements in the structure, guanosine triphosphatase (GTPase) activity, posttranslational modifications, regulatory factors, and inhibitors of eEF2 are summarized. These findings provide a comprehensive cognition on the critical role of eEF2 and its potential as a therapeutic target in cancer. Furthermore, this review highlights important unanswered questions that warrant investigation in future research.

Keywords: Cancer; Elongation factor 2; Inhibitors; Protein elongation; Regulators.

Fig. 1

A The protein structures similarity of eEF2 between yeast, human, Drosophila, and E. coli. B The amino composition and domain similarity: domain I (G, G′); domain II, domain III, domain IV, and domain V. The three-dimensional (3D) structure of eEF2 and the binding site of GTP in the structure. The colors of different protein domains are consistent in A and B. The figure was created with ACDSee Systems Canvas

Fig. 2

The common modification categories and modification amino sites of eEF2. The detail amino sites were shown beside the corresponding modification. The figure was created with BioRender.com

Fig. 3

The directed kinases and detail amino sites that regulating eEF2 phosphorylation. eEF2K, CDK1/2 and CSK elevated the phosphorylation of eEF2. The figure was created with BioRender.com

Fig. 4

The signal pathways of PP2A regulates the dephosphorylation of eEF2. The figure was created with BioRender.com

Fig. 5

The other reported proteins that contacted with eEF2 and regulated its functions. The figure was created with BioRender.com

Fig. 6

The chemical structure and CAS number of Sordarin, RA-VII, Toosendanin, and DDD107498. The figure was created with ACDSee Systems Canvas

Fig. 7

Illustration of eEF2 targeting strategies in cancer therapy: modulation of posttranslational modification (PTM), GTPase activity, and inhibitor strategies. A Posttranslational modifications of eEF2: phosphorylation of eEF2 by eEF2K renders it inactive, suppressing its integration into the elongation complex and thereby inhibiting cancer cell proliferation and progression. In contrast, diphthamide modification on eEF2 facilitates its binding to mRNA and stabilizes its interaction with the ribosome complex, promoting cancer cell survival and proliferation. Similarly, methylation of eEF2, catalyzed by FAM86A, enhances eEF2’s interaction with the ribosome, further driving cancer progression. B GTPase activity of eEF2: eEF2 binds to GTP, facilitating the formation of the ribosome–protein synthesis complex. Following GTP hydrolysis to GDP, eEF2 dissociates from the ribosome, initiating the next elongation cycle. Aberrant activation of this process results in abnormal protein synthesis, leading to enhanced cancer cell proliferation. C Therapeutic targeting of eEF2 and its complexes: targeting eEF2 or its associated complexes can suppress cancer proliferation by disrupting translation processes, inducing cell cycle arrest, and triggering apoptosis. The figure was created with BioRender.com