新型的eEF2K抑制剂BL-EKI03,在乳腺癌中诱导自噬和凋亡作用机制研究
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- 英文论文题名：A novel eEF2K inhibitor,BL-EKI03 induces autophagy and apoptosis in breast cancer
- 论文作者：张岚 ; 赵玉倩 ; 刘博
- 年：2016
- 作者机构：四川大学华西医院生物治疗国家重点实验室生物治疗协同创新中心;
- 论文关键词：真核延伸因子-2激酶(eEF2K) ; eEF2K抑制剂(BL-EKI03) ; 自噬 ; 凋亡 ; 乳腺癌
- 英文论文关键词：Eukaryotic elongation factor-2 kinase(eEF2K) ; eEF2K inhibitor(BL-EKI03) ; Autophagy ; Apoptosis ; Breast cancer
- 会议召开时间：2016-09-27
- 会议录名称：中国药学会第十三届青年药学科研成果交流会论文集
- 语种：中文
- 分类号：R96
- 学会代码：YYWS
- 会议名称：中国药学会第十三届青年药学科研成果交流会
- 会议地点：中国江西南昌
- 主办单位：中国药学会
- 学会名称：中国药学会
- 页数：6
- 文件大小：2026k
- 原文格式：O
- 会议级别：全国
摘要
真核延伸因子-2激酶(eEF2K)可以使癌细胞适应代谢压力,在一些癌症类型中发现了eEF2K的高表达,eEF2K有助于癌症的发生,可作为一个潜在的治疗靶点,然而抑制eEF2K的抗肿瘤药物的开发依然停留在初期。于此,我们通过计算机辅助药物筛选并合成了一系列靶向eEF2K的候选药物,最终找到了一个新的与eEF2K有良好亲和力的eEF2K抑制剂(BL-EKI03)。在MCF-7,MDA-MB-436细胞中,我们发现BL-EKI03有显著的抗增殖活性,并且可以诱导细胞自噬和细胞凋亡。更重要的是,我们验证了BL-EKI03通过eEE2K介导的AMPK-mTOR-ULK复合体通路来诱导死亡性自噬的机制。这些结果证明了一个新型的eEF2K抑制剂(BL-EKI03)通过诱导自噬和凋亡发挥抗乳腺癌作用,这个抑制剂为未来的肿瘤治疗提供了新希望。
Eukaryotic elongation factor-2 kinase(eEF2K) activity may confer cancer celladaptation to metabolic stress,and high expression of eEF2 K has been found in severaltypes of cancer.Thus,eEF2 K may contribute to carcinogenesis and also represent apotential target;however,inhibition of eEF2 K for cancer drug discovery still remains in itsinfancy.Herein,we computationally screened a series of candidate compounds targetingeEF2 K,synthesized series of compounds,and eventually discovered a novel eEF2Kinhibitor(BL-EKI03) with a good affinity for eEF2 K.Subsequently,we found that BL-EKI03 has remarkable anti-proliferative activities and induces autophagy and apoptosis inMCF-7 and MDA-MB-436 cells.More importantly,we demonstrated that the mechanismfor BL-EKI03-induced autophagic cell death involves eEF2K-mediated AMPK-mTOR-ULKcomplex pathways.Altogether,these results demonstrate that a novel eEF2 K inhibitor(BL-EKI03)induces autophagy and apoptosis in breast cancer and that this inhibitor holds a promisefor future cancer therapy.
Eukaryotic elongation factor-2 kinase(eEF2K) activity may confer cancer celladaptation to metabolic stress,and high expression of eEF2 K has been found in severaltypes of cancer.Thus,eEF2 K may contribute to carcinogenesis and also represent apotential target;however,inhibition of eEF2 K for cancer drug discovery still remains in itsinfancy.Herein,we computationally screened a series of candidate compounds targetingeEF2 K,synthesized series of compounds,and eventually discovered a novel eEF2Kinhibitor(BL-EKI03) with a good affinity for eEF2 K.Subsequently,we found that BL-EKI03 has remarkable anti-proliferative activities and induces autophagy and apoptosis inMCF-7 and MDA-MB-436 cells.More importantly,we demonstrated that the mechanismfor BL-EKI03-induced autophagic cell death involves eEF2K-mediated AMPK-mTOR-ULKcomplex pathways.Altogether,these results demonstrate that a novel eEF2 K inhibitor(BL-EKI03)induces autophagy and apoptosis in breast cancer and that this inhibitor holds a promisefor future cancer therapy.
引文
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[2]Ryazanov AG 1,Shestakova EA,Natapov PG.Phosphorylation of elongation factor 2 by EF-2 kinase affects rate of translation.Nature,1988,334:170-173.
[3]Kaul G,Pattan G,Rafeequi T.Eukaryotic elongation factor-2(eEF2):its regulation and peptide chain elongation.Cell BiochemFunct,2011,29:227-234.
[4]Hait WN,Wu H,Jin S,Yang JM.Elongation factor-2 kinase:its role in protein synthesis and autophagy.Autophagy,2006,2:294-296.
[5]Hait WN,Versele M,Yang JM.Surviving Metabolic Stress:Of Mice(Squirrels)and Men.Cancer discov,2014,4:646-649.
[6]Leprivier G,et al.The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation.Cell,2013,153:1064-1079.
[7]Manning BD.Adaptation to starvation:translating a matter of life or death.Cancer Cell,2013,23:713-715.
[8]Browne GJ,Finn SG,Proud CG.Stimulation of the AMP-activated protein kinase leads to activation of eukaryotic elongation factor 2kinase and to its phosphorylation at a novel site,serine 398.J BiolChem,2004,279:12220-12231.
[9]Browne GJ,Proud CG.A novel mTOR-regulated phosphorylation site in elongation factor 2 kinase modulates the activity of the kinase and its binding to calmodulin.Mol Cell Biol,2004,24:2986-97.
[10]Zhu H,et al.Eukaryotic elongation factor 2 kinase confers tolerance to stress conditions in cancer cells.Cell Stress Chaperones,2015,20:217-220.19
[11]Fu LL,Xie T,Zhang SY,Liu B.Eukaryotic elongation factor-2 kinase(eEF2K):a potential therapeutic target in cancer.Apoptosis,2014,19:1527-1531.
[12]Wang X,et al.Eukaryotic elongation factor 2 kinase activity is controlled by multiple inputs from oncogenic signaling.Mol Cell Biol,2014,34:4088-4103.
[13]Zhang Y,et al.Inhibition of eEF-2 kinase sensitizes human glioma cells to TRAIL and down-regulates Bcl-XL expression.BiochemBiophys Res Commun,2011,414:129-134.
[14]Wu H,Yang JM,Jin S,Zhang H,Hait WN.Elongation factor-2 kinase regulates autophagy in human glioblastoma cells.Cancer Res,2006,66:3015-3023.
[15]Liu JC,et al.Combined deletion of Pten and p53 in mammary epithelium accelerates triple-negative breast cancer with dependency on eEF2K.EMBO Mol Med,2014,6:1542-1560.
[16]Russnes HG,Caldas C.eEF2K-a new target in breast cancers with combined inactivation of p53 and PTEN.EMBO Mol Med,2014,6:1512-1514.
[17]Chen Z,et al.l-Benzyl-3-cetyl-2-methylimidazolium iodide(NH125)induces phosphorylation of eukaryotic elongation factor-2(eEF2):a cautionary note on the anticancer mechanism of an eEF2 kinase inhibitor.J BiolChem,2011,286:43951-43958.
[18]Devkota AK,et al.Investigating the kinetic mechanism of inhibition of elongation factor 2 kinase by NH125:evidence of a common in vitro artifact.Biochemistry,2012,51:2100-2112.
[19]Edupuganti R,et al.Synthesis and biological evaluation of pyrido[2,3-d]pyrimidine-2,4-dione derivatives as eEF-2K inhibitors.Bioorg Med Chem,2014,22:4910-2916.
[20]Chu HP,et al.Germline quality control:eEF2K stands guard to eliminate defective oocytes.Dev Cell,2014,28:561-572.
[21]Cheng Y,et al.eEF-2 kinase dictates cross-talk between autophagy and apoptosis induced by Akt Inhibition,thereby modulating cytotoxicity ofnovelAkt inhibitor MK-2206.Cancer Res,2011,71:2654-2663.
[22]Cheng Y,Yan L,Ren X,Yang JM.eEF-2 kinase,another meddler in the"yin and yang"of Akt-mediated cell fate.Autophagy,2011,7:660-661.
[2]Ryazanov AG 1,Shestakova EA,Natapov PG.Phosphorylation of elongation factor 2 by EF-2 kinase affects rate of translation.Nature,1988,334:170-173.
[3]Kaul G,Pattan G,Rafeequi T.Eukaryotic elongation factor-2(eEF2):its regulation and peptide chain elongation.Cell BiochemFunct,2011,29:227-234.
[4]Hait WN,Wu H,Jin S,Yang JM.Elongation factor-2 kinase:its role in protein synthesis and autophagy.Autophagy,2006,2:294-296.
[5]Hait WN,Versele M,Yang JM.Surviving Metabolic Stress:Of Mice(Squirrels)and Men.Cancer discov,2014,4:646-649.
[6]Leprivier G,et al.The eEF2 kinase confers resistance to nutrient deprivation by blocking translation elongation.Cell,2013,153:1064-1079.
[7]Manning BD.Adaptation to starvation:translating a matter of life or death.Cancer Cell,2013,23:713-715.
[8]Browne GJ,Finn SG,Proud CG.Stimulation of the AMP-activated protein kinase leads to activation of eukaryotic elongation factor 2kinase and to its phosphorylation at a novel site,serine 398.J BiolChem,2004,279:12220-12231.
[9]Browne GJ,Proud CG.A novel mTOR-regulated phosphorylation site in elongation factor 2 kinase modulates the activity of the kinase and its binding to calmodulin.Mol Cell Biol,2004,24:2986-97.
[10]Zhu H,et al.Eukaryotic elongation factor 2 kinase confers tolerance to stress conditions in cancer cells.Cell Stress Chaperones,2015,20:217-220.19
[11]Fu LL,Xie T,Zhang SY,Liu B.Eukaryotic elongation factor-2 kinase(eEF2K):a potential therapeutic target in cancer.Apoptosis,2014,19:1527-1531.
[12]Wang X,et al.Eukaryotic elongation factor 2 kinase activity is controlled by multiple inputs from oncogenic signaling.Mol Cell Biol,2014,34:4088-4103.
[13]Zhang Y,et al.Inhibition of eEF-2 kinase sensitizes human glioma cells to TRAIL and down-regulates Bcl-XL expression.BiochemBiophys Res Commun,2011,414:129-134.
[14]Wu H,Yang JM,Jin S,Zhang H,Hait WN.Elongation factor-2 kinase regulates autophagy in human glioblastoma cells.Cancer Res,2006,66:3015-3023.
[15]Liu JC,et al.Combined deletion of Pten and p53 in mammary epithelium accelerates triple-negative breast cancer with dependency on eEF2K.EMBO Mol Med,2014,6:1542-1560.
[16]Russnes HG,Caldas C.eEF2K-a new target in breast cancers with combined inactivation of p53 and PTEN.EMBO Mol Med,2014,6:1512-1514.
[17]Chen Z,et al.l-Benzyl-3-cetyl-2-methylimidazolium iodide(NH125)induces phosphorylation of eukaryotic elongation factor-2(eEF2):a cautionary note on the anticancer mechanism of an eEF2 kinase inhibitor.J BiolChem,2011,286:43951-43958.
[18]Devkota AK,et al.Investigating the kinetic mechanism of inhibition of elongation factor 2 kinase by NH125:evidence of a common in vitro artifact.Biochemistry,2012,51:2100-2112.
[19]Edupuganti R,et al.Synthesis and biological evaluation of pyrido[2,3-d]pyrimidine-2,4-dione derivatives as eEF-2K inhibitors.Bioorg Med Chem,2014,22:4910-2916.
[20]Chu HP,et al.Germline quality control:eEF2K stands guard to eliminate defective oocytes.Dev Cell,2014,28:561-572.
[21]Cheng Y,et al.eEF-2 kinase dictates cross-talk between autophagy and apoptosis induced by Akt Inhibition,thereby modulating cytotoxicity ofnovelAkt inhibitor MK-2206.Cancer Res,2011,71:2654-2663.
[22]Cheng Y,Yan L,Ren X,Yang JM.eEF-2 kinase,another meddler in the"yin and yang"of Akt-mediated cell fate.Autophagy,2011,7:660-661.