Inducement of ER Stress by PAD Inhibitor BB-Cl-Amidine to Effectively Kill AML Cells
Inducement of ER Stress by PAD Inhibitor BB-Cl-Amidine to Effectively Kill AML Cells
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DOI：
10.1007/s11596-022-2637-x
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发表时间：
2022-10
影响因子：
2.4
通讯作者：
Yanni Sun;Yan-ni Ma;X. Jia;Qiong Yao;Jieping Chen;Hui Li
中科院分区：
文献类型：
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作者：
Yanni Sun;Yan-ni Ma;X. Jia;Qiong Yao;Jieping Chen;Hui Li
急性髓细胞白血病（AML）是一种高度异质性和复发性的血液恶性肿瘤。尽管新型化疗药物的出现，AML患者的完全缓解（CR）仍然不令人满意。因此，迫切需要发现新的治疗靶点或药物来治疗急性粒细胞白血病。这些表观遗传学变化如DNA甲基化和组蛋白修饰在AML中起着至关重要的作用。肽基精氨酸脱氨酶（PAD）是组蛋白脱甲基酶家族中的一个成员，PAD 2和PAD 4在AML患者中的表达明显升高，提示PAD在AML的发生和维持中具有潜在的作用，并可能成为新的治疗靶点。BB-Cl-A能有效诱导AML细胞凋亡。结果PAD 2在AML中起重要作用。此外，我们发现BB-Cl-A可以激活内质网（ER）应激反应，如磷酸化PERK（p-PERK）和eIF 2 α（p-eIF 2 α）的增加所证明的。作为ER应激激活的结果，BB-Cl-A有效地诱导AML细胞凋亡。ConclusionOur研究结果表明，PAD 2在ER稳态维持和凋亡预防中发挥作用。因此，用BB-Cl-A靶向PAD 2可以代表用于治疗AML的新的治疗策略。
ObjectiveAcute 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.MethodsAML cells were treatedin vitrowith 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.ResultsPAD2 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.ConclusionOur 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.