Thapsigargin induces apoptosis in adrenocortical carcinoma by activating endoplasmic reticulum stress and the JNK signaling pathway: an in vitro and in vivo study
Thapsigargin induces apoptosis in adrenocortical carcinoma by activating endoplasmic reticulum stress and the JNK signaling pathway: an in vitro and in vivo study
复制标题
毒胡萝卜素通过激活内质网应激和 JNK 信号通路诱导肾上腺皮质癌凋亡：体外和体内研究
DOI：
10.2147/dddt.s209947
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发表时间：
2019-01-01
影响因子：
4.8
通讯作者：
Luo, Zuojie
中科院分区：
文献类型：
--
作者：
Wu, Lili;Huang, Xuemei;Luo, Zuojie
目的毒胡萝卜素（Thapsigargin，TG）是存在于植物毒胡萝卜（ThapsiagarganicaL.）对多种肿瘤细胞系具有潜在的抗癌活性。TG通过抑制肿瘤生长诱导内质网（ER）应激和细胞凋亡。然而，TG在人肾上腺皮质癌（ACC）细胞中的凋亡作用尚不清楚。方法采用SW-13和NCI-H295 R两种人ACC细胞系，探讨TG在ACC中的潜在作用，并建立SW-13细胞小鼠异种移植模型，验证TG在体内的作用。使用Cell Counting Kit-8和Transwell测定法检测细胞活力。流式细胞术和Hoechst 33，258染色检测细胞凋亡。RT-qPCR和Western blot检测TG诱导ACC细胞凋亡的机制。结果TG呈剂量依赖性地抑制ACC细胞的增殖、迁移和侵袭。TG显著增加ACC细胞线粒体凋亡率和ER应激活性，并抑制体内ACC异种移植物生长。此外，Jun N-末端激酶（JNK）信号相关基因和蛋白的表达上调与TG的治疗。结论TG通过激活JNK信号通路诱导ACC细胞凋亡，从而抑制ACC细胞的存活。因此，TG有望成为ACC治疗的潜在候选药物。
Objective Thapsigargin (TG) is a natural product that exists in most parts of the plant Thapsia garganica L. and possesses potential anticancer activities against variety tumor cell lines. TG induces endoplasmic reticulum (ER) stress and apoptosis by inhibiting cancer growth. However, the antineoplastic effect of TG in human adrenocortical carcinoma (ACC) cells is still unknown. Methods In this study, two human ACC cell lines including SW-13 and NCI-H295R were employed to explore the potential role of TG in ACC. A mouse xenograft model of SW-13 cells was established to verify the role of TG in vivo. The cell viability was tested using Cell Counting Kit-8 and Transwell assays. Flow cytometry and Hoechst 33,258 staining were employed to analyze cell apoptosis. RT-qPCR and Western blot (WB) were performed to explore the underlying mechanism of TG-induced apoptosis in ACC cells. Results The results indicated that TG dose-dependently inhibited proliferation, migration and invasion in human ACC cells. TG significantly increased the mitochondrial rate of apoptosis and ER stress activity in ACC cells and suppressed ACC xenograft growth in vivo. In addition, the expression of Jun N-terminal kinase (JNK) signaling-related genes and proteins was upregulated by the treatment with TG. Conclusion Our findings suggest that TG inhibits the viability of ACC cells by inducing apoptosis through the activation of JNK signaling. Thus, TG is expected to be a potential candidate for the treatment of ACC.