LiCl induces apoptosis via CHOP/NOXA/Mcl-1 axis in human choroidal melanoma cells.
LiCl induces apoptosis via CHOP/NOXA/Mcl-1 axis in human choroidal melanoma cells.
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DOI：
10.1186/s12935-021-01778-2
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发表时间：
2021-02-08
影响因子：
5.8
通讯作者：
Zhang H
中科院分区：
文献类型：
--
作者：
Zhang Q;Zhang Q;Li H;Zhao X;Zhang H
脉络膜黑色素瘤是成人最常见的原发性眼内恶性肿瘤。氯化锂通过抑制糖原合成酶激酶3 β促进人白血病NB 4细胞凋亡在这项研究中，我们的目的是了解氯化锂是否对脉络膜黑色素瘤细胞发挥抗癌作用，并阐明潜在的分子机制。用LiCl处理人脉络膜黑色素瘤细胞，用MTT测定法评估细胞存活。通过平板集落形成测定来测量细胞繁殖活力。流式细胞仪检测细胞凋亡情况，蛋白质印迹法检测蛋白质表达。建立了人脉络膜黑色素瘤异种移植模型，以证明LiCl对人脉络膜黑色素瘤的体内作用。我们发现，氯化锂抑制细胞存活和克隆形成的潜力，并诱导人脉络膜黑色素瘤细胞凋亡。氯化锂也减少脉络膜黑色素瘤细胞在体内的增殖。此外，NOXA的上调和Mcl-1的下调是导致LiCl诱导的细胞凋亡的原因。Mcl-1过表达明显减弱了LiCl诱导的细胞凋亡和caspase 8、caspase 9、caspase 3和PARP的裂解。此外，内质网应激标志物IRE 1 α、Bip、p-eIF 2 α、ATF 4和CHOP的蛋白表达在LiCl处理后上调。当CHOP表达被敲低并且用LiCl处理细胞时，与溶剂处理组相比，NOXA的蛋白水平部分增加，并且Mcl-1表达增加，而由LiCl诱导的半胱天冬酶8、半胱天冬酶9、半胱天冬酶3和PARP的切割减少。延长的ER应激导致细胞凋亡途径的激活。总之，氯化锂诱导内质网应激反应，同时激活内在凋亡。此外，CHOP/NOXA/Mcl-1轴有助于LiCl诱导的细胞凋亡在体外和体内。本研究提供了重要的机制洞察潜在的癌症治疗涉及氯化锂，并提高了人类脉络膜黑色素瘤的理解。
Choroidal melanoma is the most common primary intraocular malignancy that occurs in adults. Lithium Chloride Promotes Apoptosis in Human Leukemia NB4 Cells by Inhibiting Glycogen Synthase Kinase-3 Beta. In this study, we aimed to understand whether LiCl exerts anticancer effects on choroidal melanoma cells and elucidate the underlying molecular mechanisms. Human choroidal melanoma cells were treated with LiCl, and cell survival was assessed with MTT assays. Cell reproductive viability was measured by plate colony formation assays. Cell apoptosis was evaluated using flow cytometry, and proteins were detected using western blotting. A human choroidal melanoma xenograft model was established to demonstrate the effect of LiCl on human choroidal melanoma in vivo. We found that LiCl inhibited cell survival and clonogenic potential and induced apoptosis in human choroidal melanoma cells. LiCl also reduced the proliferation of choroidal melanoma cells in vivo. Moreover, the upregulation of NOXA and downregulation of Mcl-1 were responsible for LiCl-induced apoptosis. Mcl-1 overexpression obviously impaired LiCl-induced apoptosis and cleavage of caspase8, caspase9, caspase3 and PARP. Moreover, the protein expression of endoplasmic reticulum stress markers, including IRE1α, Bip, p-eIF2α, ATF4 and CHOP, were upregulated following treatment with LiCl. When CHOP expression was knocked down and cells were treated with LiCl, the protein level of NOXA was partially increased, and Mcl-1 expression was increased, while the cleavage of caspase8, caspase9, caspase3 and PARP that was induced by the LiCl was reduced compared with the vehicle treated group. Prolonged ER stress results in the activation of the apoptotic pathway. In summary, LiCl induced an endoplasmic reticulum stress response while activating intrinsic apoptosis. Furthermore, the CHOP/NOXA/Mcl-1 axis contributed to LiCl-induced apoptosis both in vitro and in vivo. The present study provides important mechanistic insight into potential cancer treatments involving LiCl and enhances the understanding of human choroidal melanoma.
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影响因子：
2.1
作者：
Asadi S;Vaez-zadeh M;Masoudi SF;Rahmani F;Knaup C;Meigooni AS
通讯作者：
Meigooni AS
影响因子：
3.6
作者：
Li L;Song H;Zhong L;Yang R;Yang XQ;Jiang KL;Liu BZ
通讯作者：
Liu BZ
影响因子：
8
作者：
Wang H;Liu Z;Gou Y;Qin Y;Xu Y;Liu J;Wu JZ
通讯作者：
Wu JZ
影响因子：
0.6
作者：
Hamza, Hany S.;Elhusseiny, Abdelrahman M.
通讯作者：
Elhusseiny, Abdelrahman M.
影响因子：
120.1
作者：
Cohen, P;Goedert, M
通讯作者：
Goedert, M