真核延伸因子2激酶是治疗肿瘤的潜在新靶标

doi:10.16352/j.issn.1001-6325.2024.07.1039

基础医学与临床 ›› 2024, Vol. 44 ›› Issue (7): 1039-1043.doi: 10.16352/j.issn.1001-6325.2024.07.1039

真核延伸因子2激酶是治疗肿瘤的潜在新靶标

李阳, 朱蕾^*

中国医学科学院基础医学研究所北京协和医学院基础学院药理系,北京 100005

收稿日期:2024-03-29 修回日期:2024-05-21 出版日期:2024-07-05 发布日期:2024-06-26
通讯作者: ^*leizhu2004@126.com
基金资助:
中国医学科学院医学与健康科技创新工程项目(2021-I2M-1-005);中央高水平医院临床科研业务费(2022-PUMCH-C-025)

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

LI Yang, ZHU Lei^*

Department of Pharmacology, Institute of Basic Medical Sciences CAMS, School of Basic Medicine PUMC, Beijing 100005, China

Received:2024-03-29 Revised:2024-05-21 Online:2024-07-05 Published:2024-06-26
Contact: ^*leizhu2004@126.com

摘要/Abstract

摘要： 真核延伸因子2激酶(eEF2K)是一种Ca²⁺/CaM依赖性蛋白激酶,通过磷酸化底物eEF2,从而抑制eEF2的活性阻止蛋白质的合成,促进肿瘤细胞增殖、侵袭、转移并调节肿瘤微环境。该eEF2K属于非典型蛋白激酶家族的“α-激酶”成员,与典型的蛋白激酶在序列上同源性小,靶向eEF2K可以避免因对大多数激酶影响而产生的毒副作用,因此被认为是肿瘤靶向治疗的潜在分子靶标。

关键词: eEF2K, 肿瘤微环境, 肿瘤治疗, 抑制剂

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

中图分类号:

R966

李阳, 朱蕾. 真核延伸因子2激酶是治疗肿瘤的潜在新靶标[J]. 基础医学与临床, 2024, 44(7): 1039-1043.

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.

参考文献

[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.

真核延伸因子2激酶是治疗肿瘤的潜在新靶标

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

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