LW-213 induces cell apoptosis in human cutaneous T-cell lymphomas by activating PERK-eIF2 alpha-ATF4-CHOP axis
LW-213 induces cell apoptosis in human cutaneous T-cell lymphomas by activating PERK-eIF2 alpha-ATF4-CHOP axis
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LW-213 通过激活 PERK-eIF2α-ATF4-CHOP 轴诱导人皮肤 T 细胞淋巴瘤细胞凋亡
DOI：
10.1038/s41401-020-0466-7
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发表时间：
2020
影响因子：
8.2
通讯作者：
Hui Hui
中科院分区：
文献类型：
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作者：
Yu Xiao-xuan;Zhu Meng-yuan;Wang Jia-rong;Li Hui;Hu Po;Qing Ying-jie;Wang Xiang-yuan;Wang Hong-zheng;Wang Zhan-yu;Xu Jing-yan;Guo Qing-long;Hui Hui
皮肤T细胞淋巴瘤（CTCL）是一组异质性的结节性非霍奇金淋巴瘤，其中单克隆T淋巴细胞浸润皮肤。汉黄芩素衍生物LW-213可诱导慢性粒细胞白血病（CML）细胞凋亡。本研究探讨LW-213对CTCL细胞的作用及其机制。我们发现LW-213（1-25 μM）剂量依赖性地抑制人CTCL细胞系（Hut-102、Hut-78、MyLa和HH），IC 50值约为10 μM，同时它有效地抑制T细胞淋巴瘤患者外周血来源的原代白血病细胞。我们发现LW-213诱导的细胞凋亡伴随着ROS的形成和内质网（ER）通过IP 3R-1通道释放钙离子。LW-213通过激活PERK-eIF 2 α-ATF 4通路选择性激活CHOP并诱导Hut-102细胞凋亡。有趣的是，在ROS清除剂N-乙酰半胱氨酸（NAC）或IP 3R-1抑制剂2-氨基乙基二苯硼酸酯（2-APB）存在下，细胞凋亡程度和ER应激相关蛋白的表达均减轻，表明ROS/钙依赖性ER应激参与LW-213诱导的细胞凋亡。LW-213（10 mg/kg，ip，隔日1次，共4周）对荷Hut-102细胞系异种移植瘤的NOD/SCID小鼠的生长有明显的抑制作用，并延长其存活时间。总之，我们的研究为LW-213诱导细胞凋亡的机制提供了新的见解，表明LW-213作为一种有前途的抗CTCL药物的潜力。
Cutaneous T-cell lymphoma (CTCL) is characterized by a heterogeneous group of extranodal non-Hodgkin lymphomas, in which monoclonal T lymphocytes infiltrate the skin. LW-213, a derivative of wogonin, was found to induce cell apoptosis in chronic myeloid leukemia (CML). In this study, we investigated the effects of LW-213 on CTCL cells and the underlying mechanisms. We showed that LW-213 (1–25 μM) dose-dependently inhibited human CTCL cell lines (Hut-102, Hut-78, MyLa, and HH) with IC50values of around 10 μM, meanwhile it potently inhibited primary leukemia cells derived from peripheral blood of T-cell lymphoma patients. We revealed that LW-213-induced apoptosis was accompanied by ROS formation and the release of calcium from endoplasmic reticulum (ER) through IP3R-1channel. LW-213 selectively activated CHOP and induced apoptosis in Hut-102 cells via activating PERK–eIF2α–ATF4 pathway. Interestingly, the degree of apoptosis and expression of ER stress-related proteins were alleviated in the presence of either N-acetyl cysteine (NAC), an ROS scavenger, or 2-aminoethyl diphenylborinate (2-APB), an IP3R-1 inhibitor, implicating ROS/calcium-dependent ER stress in LW-213-induced apoptosis. InNOD/SCIDmice bearing Hut-102 cell line xenografts, administration of LW-213 (10 mg/kg, ip, every other day for 4 weeks) markedly inhibited the growth of Hut-102 derived xenografts and prolonged survival. In conclusion, our study provides a new insight into the mechanism of LW-213-induced apoptosis, suggesting the potential of LW-213 as a promising agent against CTCL.