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Evaluating the Effectiveness of Cancer Drug Sensitization In Vitro and In Vivo
Published on: February 6, 2015
Differential apoptotic response of human cancer cells to organoselenium compounds
Maiko Suzuki1, Manabu Endo, Fumiaki Shinohara
1Department of Microbiology and Immunology, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
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 eIF2alpha 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.
Insights
Selenium compounds induce cancer cell death through apoptosis. This study reveals that selenium-induced apoptosis involves caspase activation and endoplasmic reticulum stress, with p53 playing a role in specific cases.
Area of Science:
- Biochemistry
- Molecular Biology
- Cancer Research
Background:
- Selenium (Se) compounds are known for their anti-cancer properties, inhibiting cell proliferation and inducing apoptosis in human cancer cells.
- The precise mechanisms by which different chemical forms of selenium (Se) activate apoptosis are not fully understood.
- Intracellular metabolism of Se compounds involves complex pathways targeting distinct molecules, leading to varying anti-carcinogenic effects across cancer types.
Purpose of the Study:
- To investigate the effects of Se-methylselenocysteine (MSC), selenomethionine (SeMet), and selenite on cell proliferation and apoptosis in human carcinoma cell lines.
- To elucidate the specific apoptotic pathways activated by these selenium compounds.
- To analyze the role of endoplasmic reticulum (ER) stress and p53 in selenium-induced apoptosis.
Main Methods:
- Human carcinoma cell lines (HSC-3, -4, A549, MCF-7) were treated with MSC, SeMet, and selenite.
- Apoptosis, caspase activity, and ER stress markers were analyzed using flow cytometry and immunoblotting.
- Cell viability was assessed in the presence of a pan-caspase inhibitor (z-VAD-fmk).
Main Results:
- SeMet induced apoptosis in p53-positive A549 cells, while MSC induced apoptosis in p53-mutated HSC-3 cells.
- High activities of caspase-3, -8, and -9 were observed, and caspase inhibition rescued HSC-3 cell viability upon MSC treatment.
- Endoplasmic reticulum (ER) stress was indicated by increased phosphorylated eIF2alpha and caspase-12 activity. Selenite and MSC reduced phosphorylated Akt levels and inhibited vascular endothelial growth factor expression.
Conclusions:
- Selenium-induced apoptosis in carcinoma cells is a caspase-dependent process.
- Both the intrinsic apoptotic pathway and the ER stress pathway play significant, concurrent roles in Se-induced apoptosis.
- p53 activation appears to have a functional role specifically in SeMet-mediated apoptosis.
