LiCl induces apoptosis via CHOP/NOXA/Mcl-1 axis in human choroidal melanoma cells

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

BAY-885, a mitogen-activated protein kinase kinase 5 inhibitor, induces apoptosis by regulating the endoplasmic reticulum stress/Mcl-1/Bim pathway in breast cancer cells

“…Notably, we discovered that BAY-885-induced ER stress is required for the downregulation of Mcl-1 and the upregulation of Bim, as indicated by the use of an ER stress inhibitor (GSK2656157), and that genetic knockdown of PERK abolished BAY-885ʹs effects on Mcl-1 and Bim expression ( Figure 4d ). In accordance with our findings, many studies found that activation of ER stress caused downregulation of Mcl-1 [ 37–39 ]. Upregulation of Mcl-1 could attenuate the apoptosis induced by ER stress in melanoma cells [ 40 ].…”

Bortezomib Inhibits Multiple Myeloma Cells by Transactivating ATF3 to Trigger miR-135a-5p- Dependent Apoptosis

“…Additionally, Noxa gene expression is mediated by ATF3 in Noxa-dependent intrinsic apoptosis, i.e., the ATF3-CHOP/Noxa axis. For example, the CHOP/NOXA/Mcl-1 axis contributes to LiCl-induced apoptosis ( 26 ), and ATF4-triggered Noxa- and DR5-dependent extrinsic apoptosis have been seen in fangchinoline-treated esophageal squamous cells ( 27 ). Because ER stress in BTZ-treated MM cell lines is beyond their self-defense capacity, the MM cell activates apoptotic signals to remove damage organelles ( 28 ).…”

Lithium chloride induces apoptosis by activating endoplasmic reticulum stress in pancreatic cancer

“…Retrospective studies have shown that bipolar disorder patients receiving lithium therapy have a significant lower risk for cancer than those not treated with lithium [9] , [10] , [11] , [12] . Recent studies have found that lithium salts can inhibit the proliferation and development of various tumors [13] , [14] , [15] , [16] , [17] , [18] . Existing research has demonstrated that lithium exerts most of its pharmacological effects by inhibiting the activity of some phosphate-transfer enzymes, including GSK3β, which require magnesium as a co-factor [19] .…”