靶向抑制ERG的小分子多肽通过下调c-Myc杀伤急性淋巴性白血病细胞的机制研究  

Study on the Mechanism of Killing Acute Lymphoblastic Leukemia Cells by Small Molecule Peptides Targeting ERG that Inhibit C-Myc Expression

作　　者：李子林 张旭 屠凌岚 程丽艳 LI Zilin;ZHANG Xu;TU Linglan;CHENG Liyan(Hangzhou Medical College,Hangzhou 310053,China)

机构地区：[1]杭州医学院,杭州310053

出　　处：《中国现代应用药学》2023年第11期1469-1474,共6页Chinese Journal of Modern Applied Pharmacy

基　　金：浙江省教育厅项目(Y202146049)。

摘　　要：目的 研究靶向抑制ERG的小分子多肽杀伤急性淋巴性白血病(acute lymphoblastic leukemia,ALL)细胞的机制。方法 CellTiter-Glo~?细胞活力测定试剂盒检测不同浓度的小分子多肽对ERG阳性的ALL细胞系增殖和活力的影响;AnnexinV/PI双染法检测小分子多肽对ERG阳性的ALL细胞系的凋亡诱导情况;裸鼠皮下瘤模型用于评估小分子多肽对ERG阳性的ALL细胞系在体内杀伤作用;Western blotting检测蛋白酶体抑制剂对小分子多肽降解ERG蛋白的拮抗作用;慢病毒包装的质粒转染ALL细胞系,干扰ERG的表达,观察其对c-Myc的影响;慢病毒包装的质粒转染ALL细胞系沉默c-Myc的表达,观察其对筑巢因子GDF15表达的影响。结果 靶向降解ERG的小分子多肽在体内外模型中均可以杀伤ALL细胞系;在质粒转染敲低ERG及c-Myc表达的细胞系,GDF15表达被明显抑制。结论 本研究明确了小分子多肽在体外和体内具有杀伤ERG阳性ALL细胞的作用,其通过蛋白酶体降解的方式抑制ERG的表达,并可能通过c-Myc来抑制筑巢因子GDF15的表达,从而发挥杀伤ERG阳性的ALL细胞系的作用。OBJECTIVE To study the mechanism of killing acute lymphoblastic leukemia(ALL)cells by targeting small molecule peptides that inhibit ERG.METHODS CellTiter-Glo®cell viability assay kit was used to detect the effect of different concentrations of small molecule polypeptides on the proliferation and viability of ERG-positive ALL cell lines;Annexin V/PI double staining method was used to detect the apoptosis induction of molecular polypeptides on ERG-positive ALL cell lines.The nude mouse subcutaneous tumor model was used to evaluate the killing effect of small-molecule polypeptides on ERG-positive ALL cell lines in vivo;Western blotting detected the proteasome inhibitors on the degradation of ERG by small-molecule polypeptides;lentiviral-packaged plasmid transfected into ALL cell lines,which interfered with the expression of ERG,and observed its effect on c-Myc;lentiviral-packaged plasmid transfected into ALL cell lines to silence c-Myc expression,and observed its effect on nesting factor GDF15 expression.RESULTS Small molecule peptides targeting ERG degradation could kill ALL cell lines in vitro and in vivo;the expression of GDF15 was significantly inhibited in the cell lines that knocked down the expression of ERG and c-Myc by plasmid transfection.CONCLUSION This study clarifies that small molecule polypeptides have the effect of killing ERG-positive ALL cells in vitro and in vivo.They inhibit the expression of ERG through proteasomal degradation,and may inhibit the nesting factor GDF15 through c-Myc,thereby killing ERG-positive ALL cell lines.

关 键 词：小分子多肽 ERG C-MYC 急性淋巴细胞性白血病 

分 类 号：R965.2[医药卫生—药理学]