Inducement of ER Stress by PAD Inhibitor BB-Cl-Amidine to Effectively Kill AML Cells
作者机构：Department of HematologySouthwest HospitalThird Military Medical University(Army Medical University)Chongqing400038China
出 版 物：《Current Medical Science》 (当代医学科学（英文）)
年 卷 期：2022年第42卷第5期
页 面：958-965页
核心收录：
学科分类：1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 100214[医学-肿瘤学] 10[医学]
基 金：supported by the National Natural Science Foundation of China(No.81972564).
主 题：acute myeloid leukemia BB-Cl-Amidine peptidylarginine deminase endoplasmic reticulum stress apoptosis
摘 要：Objective Acute myeloid leukemia(AML)is a highly heterogeneous and recurrent hematological malignancy.Despite the emergence of novel chemotherapy drugs,AML patients’complete remission(CR)remains unsatisfactory.Consequently,it is imperative to discover new therapeutic targets or medications to treat AML.Such epigenetic changes like DNA methylation and histone modification play vital roles in AML.Peptidylarginine deminase(PAD)is a protein family of histone demethylases,among which the PAD2 and PAD4 expression have been demonstrated to be elevated in AML patients,thus suggesting a potential role of PADs in the development or maintenance of AML and the potential for the identification of novel therapeutic targets.Methods AML cells were treated in vitro with the pan-PAD inhibitor BB-Cl-Amidine(BB-Cl-A).The AML cell lines were effectively induced into apoptosis by BB-Cl-A.However,the PAD4-specific inhibitor GSK484 did not.Results PAD2 played a significant role in AML.Furthermore,we found that BB-Cl-A could activate the endoplasmic reticulum(ER)stress response,as evidenced by an increase in phosphorylated PERK(p-PERK)and eIF2α(p-eIF2α).As a result of the ER stress activation,the BB-Cl-A effectively induced apoptosis in the AML cells.Conclusion Our findings indicated that PAD2 plays a role in ER homeostasis maintenance and apoptosis prevention.Therefore,targeting PAD2 with BB-Cl-A could represent a novel therapeutic strategy for treating AML.
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