Eukaryotic elongation factor 2 kinase is a potential new target for the treatment of tumors

doi:10.16352/j.issn.1001-6325.2024.07.1039

Abstract

Abstract: Eukaryotic elongation factor 2 kinase (eEF2K) is a Ca²⁺/ CAM-dependent protein kinase, which inhibits the activity of substrate eEF2 by phosphorylating eEF2 to prevent protein synthesis, promote tumor cell proliferation, invasion, metastasis and to regulate tumor microenvironment. The eEF2K is “α-kinase” member of the atypical protein kinase family and has little sequence homology with typical protein kinases. Targeting eEF2K can avoid the toxic side effects caused by most kinases, so it is considered as a potential molecular target for tumor targeted therapy.

Key words: eEF2K, tumor microenvironment, tumor treatment, inhibitor

CLC Number:

R966

LI Yang, ZHU Lei. Eukaryotic elongation factor 2 kinase is a potential new target for the treatment of tumors[J]. Basic & Clinical Medicine, 2024, 44(7): 1039-1043.

References

[1]Karakas D, Ozpolat B. Eukaryotic elongation factor-2 kinase (eEF2K) signaling in tumor and microenvironment as a novel molecular target[J]. J Mol Med (Berl), 2020,98:775-787.
[2]Piserchio A, Long KJ, Browning LS, et al. ADP enhances the allosteric activation of eukaryotic elongation factor 2 kinase by calmodulin[J]. Proc Natl Acad Sci U S A,2023,25;120:e2300902120. doi:10.1073/pnas.2300902120.
[3]Tekedereli I, Alpay SN, Tavares CD, et al. Targeted silencing of elongation factor 2 kinase suppresses growth and sensitizes tumors to doxorubicin in an orthotopic model of breast cancer[J]. PLoS One, 2012,7:e41171. doi: 10.1371/journal.pone.0041171.
[4]Zhang Y, Cheng Y, Zhang L, et al. Inhibition of eEF-2 kinase sensitizes human glioma cells to TRAIL and down-regulates Bcl-xL expression[J]. Biochem Biophys Res Commun, 2011,414:129-134.
[5]Ashour AA, Abdel-Aziz AA, Mansour AM, et al. Target-ing elongation factor-2 kinase (eEF-2K) induces apoptosis in human pancreatic cancer cells[J]. Apoptosis,2014,19:241-258.
[6]Tong S, Zhou T, Meng Y, et al. AMPK decreases ERK1/2 activity and cancer cell sensitivity to nutrition deprivation by mediating a positive feedback loop involving eEF2K[J]. Oncol Lett, 2020,20:61-66.
[7]Ju Y, Ben-David Y, Rotin D, et al. Inhibition of eEF2K synergizes with glutaminase inhibitors or 4EBP1 depletion to suppress growth of triple-negative breast cancer cells[J]. Sci Rep, 202,11:9181. doi: 10.1038/s41598-021-88816-1.
[8]Wang RX, Xu XE, Huang L, et al. eEF2 kinase mediated autophagy as a potential therapeutic target for paclitaxel-resistant triple-negative breast cancer[J]. Ann Transl Med, 2019,7:783. doi: 10.21037/atm.2019.11.39.
[9]Xie CM, Liu XY, Sham KW, et al. Silencing of eEF2K (eukaryotic elongation factor-2 kinase) reveals AMPK-ULK1-dependent autophagy in colon cancer cells[J]. Autophagy, 2014,10:1495-1508.
[10]Sun D, Zhu L, Zhao Y, et al. Fluoxetine induces autophagic cell death via eEF2K-AMPK-mTOR-ULK complex axis in triple negative breast cancer[J]. Cell Prolif, 2018,51:e12402. doi: 10.1111/cpr.12402.
[11]Ashour AA, Gurbuz N, Alpay SN, et al. Elongation factor-2 kinase regulates TG2/β1 integrin/Src/uPAR pathway and epithelial-mesenchymal transition mediating pancreatic cancer cells invasion[J]. J Cell Mol Med, 2014,18:2235-2251.
[12]Deng G, Zeng F, He Y, et al. EEF2K silencing inhibits tumour progression through repressing SPP1 and synergises with BET inhibitors in melanoma[J]. Clin Transl Med, 2022,12:e722. doi: 10.1002/ctm2.722.
[13]Wang B, Gu X, Xiang BL, et al. eEF-2K knockdown synergizes with STS treatment to inhibit cell proliferation, migration, and invasion via the TG2/ERK pathway in A549 cells[J]. J Biochem Mol Toxicol, 2022,36:e23158.doi:10.1002/jbt.23158.
[14]Zhou Y, Li Y, Xu S, et al. Eukaryotic elongation factor 2 kinase promotes angiogenesis in hepatocellular carcinoma via PI3K/Akt and STAT3[J]. Int J Cancer, 2020,146:1383-1395.
[15]Chen X, Wang K, Jiang S, et al. eEF2K promotes PD-L1 stabilization through inactivating GSK3β in melanoma[J]. J Immunother Cancer, 2022,10:e004026.doi:10.1136/jitc-2021-004026.
[16]Xu Y, Sun F, Tian Y, et al. Enhanced NK cell activation via eEF2K-mediated potentiation of the cGAS-STING pathway in hepatocellular carcinoma[J]. Int Immunopharmacol, 2024,129:11. doi: 10.1016/j.intimp.2024.111628.
[17]Das JK, Ren Y, Kumar A, et al. Elongation factor-2 kinase is a critical determinant of the fate and antitumor immunity of CD8⁺ T cells[J]. Sci Adv, 2022,8:eabl9783.doi:10.1126/sciadv.abl9783.
[18]Zhu S, Liao M, Tan H, et al. Inhibiting eukaryotic elongation factor 2 kinase:an update on pharmacological small-molecule compounds in cancer[J]. J Med Chem,2021,64:8870-8883.doi:10.1021/acs.jmedchem.DC02218.
[19]Liu Z, Jiang A, Wang Y, et al. In silico, synthesis and anticancer evaluation of benzamide tryptamine derivatives as novel eEF2K inhibitors[J]. Bioorg Med Chem Lett, 2022,67:128759. doi: 10.1016/j.bmcl.2022.128759.
[20]Fu Q, Liu X, Li Y, et al. Discovery of new inhibitors of eEF2K from Traditional Chinese Medicine based on in silico screening and in vitro experimental validation[J]. Molecules,2022,27:4886. doi: 10.3390/molecules27154886.
[21]Piserchio A, Isiorho EA, Long K, et al. Structural basis for the calmodulin-mediated activation of eukaryotic elongation factor 2 kinase[J]. Sci Adv, 2022,8:eabo2039. doi: 10.1126/sciadv.abo2039.
[22]Pan Z, Chen Y, Liu J, et al. Design, synthesis, and biological evaluation of polo-like kinase 1/eukaryotic elongation factor 2 kinase (PLK1/EEF2K) dual inhibitors for regulating breast cancer cells apoptosis and autophagy[J]. Eur J Med Chem, 2018,144:517-528.
[23]Cao MJ, Zhu T, Liu JT, et al. New sorbicillinoid derivatives with GLP-1R and eEF2K affinities from a sponge-derived fungus Penicillium chrysogenum 581F1[J]. Nat Prod Res,2020,34:2880-2886.
[24]Ye WL, Zhang LX, Guan YD, et al. Virtual screening and experimental validation of eEF2K inhibitors by combining homology modeling, QSAR and molecular docking from FDA approved drugs[J].N J Chem,2019,43:19097-19106.
[25]Zhong C, Zhu R, Jiang T, et al. Design and characterization of a novel eEF2K degrader with potent therapeu-tic efficacy against triple-negative breast cancer[J]. Adv Sci (Weinh),2024,11:e2305035. doi: 10.1002/advs.202305035.