Inducement of ER Stress by PAD Inhibitor BB-Cl-Amidine to Effectively Kill AML Cells

• Published in: Current medical science Vol. 42; no. 5; pp. 958 - 965
• Main Authors: Sun, Yan-ni, Ma, Yan-ni, Jia, Xiao-qing, Yao, Qi, Chen, Jie-ping, Li, Hui
• Format: Journal Article
• Language: English
• Published: Wuhan Huazhong University of Science and Technology 01.10.2022; Department of Hematology,Southwest Hospital,Third Military Medical University(Army Medical University),Chongqing 400038,China
• Subjects: Medicine; Medicine & Public Health; apoptosis; BB-Cl-Amidine; acute myeloid leukemia; peptidylarginine deminase; endoplasmic reticulum stress
• ISSN: 2096-5230; 1672-0733; 2523-899X; 1993-1352
• DOI: 10.1007/s11596-022-2637-x

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.