Abstract
Purpose
Selenium (Se) compounds are well known to inhibit cell proliferation and induce cell death in human cancer cells. Respective chemical forms of Se are intracellularly metabolized via complicated pathways, which target distinct molecules and exhibit varying degrees of anti-carcinogenicity in different cancer types; however, the precise mechanisms by which Se activates apoptosis remain poorly understood.
Methods
The effects of Se compounds, Se-methylselenocysteine (MSC), selenomethionine (SeMet), and selenite on cell proliferation, apoptosis and its pathway in established human carcinoma cell lines (HSC-3, -4, A549, and MCF-7) were investigated. Cancer cells were treated with each Se compound during different periods. Cell apoptosis, caspase activity and ER stress markers were analyzed by flow cytometric or immunoblotting analysis, respectively.
Results
We examined four cell lines for their sensitivity to MSC and SeMet in comparison with selenite. SeMet increased apoptotic cells in p53-positive A549 cells, whereas MSC increased apoptotic cells in p53-mutated HSC-3 cells. High activities of caspase-3, -8 and -9 were observed during apoptosis, and a pan-caspase inhibitor, z-VAD-fmk, rescued the cell viability of HSC-3 cells exposed to MSC. In addition, the occurrence of endoplasmic reticulum (ER) stress was suggested by the observation that levels of phosphorylated eIF2α and caspase-12 activity are increased in Se-treated cells. Selenite and MSC were accompanied with the concurrent reduction of phosphorylated Akt levels, and the inhibitory effects of these Se compounds on vascular endothelial growth factor expression were observed with identical patterns.
Conclusion
The present findings demonstrate that Se-induced apoptosis in carcinoma cells is basically a caspase-dependent process involving complicated mechanisms. Activation of both the intrinsic apoptotic pathway and ER stress pathway plays a major and concurrent role, while p53 activation seems to have only a functional role in SeMet.
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Acknowledgments
We thank Mr. D. Mrozek for editing the manuscript. This work was supported in part by a Grant-in-Aids for Scientific Research (20659309) from the Japan Society for the Promotion of Science and (19791480 and 19791482) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.
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280_2009_1183_MOESM1_ESM.tif
Fig. S1 Increased expression of phospho-eIF2α in SeMet-treated A549 cells. Cells were treated with SeMet (100 μM) for 24 h. Total cell lysates were prepared for phosphorylation of eIF2α, and equal amounts of extracts were loaded for Western blotting with the indicated antibodies (TIFF 68 kb)
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Suzuki, M., Endo, M., Shinohara, F. et al. Differential apoptotic response of human cancer cells to organoselenium compounds. Cancer Chemother Pharmacol 66, 475–484 (2010). https://doi.org/10.1007/s00280-009-1183-6
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DOI: https://doi.org/10.1007/s00280-009-1183-6