Differential apoptotic response of human cancer cells to organoselenium compounds.
OBJECTIVE
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.


CONCLUSIONS
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.
Suzuki
Maiko
M
Department of Microbiology and Immunology, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan.
Endo
Manabu
M
Shinohara
Fumiaki
F
Echigo
Seishi
S
Rikiishi
Hidemi
H
D016588:Anticarcinogenic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D053148:Caspase 3 / Q000187:drug effects; D053181:Caspase 8 / Q000187:drug effects / Q000378:metabolism; D053453:Caspase 9 / Q000187:drug effects / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003545:Cysteine / Q000031:analogs & derivatives* / Q000494:pharmacology; D005434:Flow Cytometry; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016566:Organoselenium Compounds / Q000494:pharmacology*; D017279:Selenocysteine / Q000031:analogs & derivatives; D012645:Selenomethionine / Q000494:pharmacology*; D018038:Sodium Selenite / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
D016588:Anticarcinogenic Agents; D016566:Organoselenium Compounds; D016159:Tumor Suppressor Protein p53; D017279:Selenocysteine; D012645:Selenomethionine; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D018038:Sodium Selenite; D003545:Cysteine; C002979:selenomethylselenocysteine