TY - JOUR
T1 - Rapamycin suppresses ROS-dependent apoptosis caused by selenomethionine in A549 lung carcinoma cells
AU - Suzuki, Maiko
AU - Endo, Manabu
AU - Shinohara, Fumiaki
AU - Echigo, Seishi
AU - Rikiishi, Hidemi
N1 - Funding Information:
Acknowledgments We thank Mr. D. Mrozek for editing the manuscript. This work was supported in part by a Grant-in-Aid for Scientific Research (20659309) from the Japan Society for the Promotion of Science and (22791948 and 21791967) from the Ministry of Education, Culture, Sports, Science, and Technology, Japan.
PY - 2011/5
Y1 - 2011/5
N2 - Purpose: Although selenium compounds possess chemotherapeutic features by inducing apoptosis in cancer cells with trivial side effects on normal cells, the mechanisms underlying its anti-cancer activity are insufficiently understood at the present. In this study, we investigated the effects of rapamycin on apoptosis induced by seleno-L-methionine (SeMet) or selenite in A549 cells. Methods: The effects of Se compounds, SeMet and selenite, on cell proliferation, apoptosis and its signaling pathway were investigated in established human adenocarcinoma cell line (A549). Cancer cells were treated with each Se during different periods. Cell apoptosis and signaling molecules were analyzed by flow cytometry (TUNEL method) or immunoblotting, respectively. Results: SeMet induces reactive oxygen species generation associated with the induction of apoptosis, because pretreatment of cells with N-acetyl-L-cysteine completely blocked SeMet-induced apoptosis. We also found that rapamycin completely suppressed the apoptosis of cells treated by SeMet, but not selenite. SeMet-induced apoptosis is significantly downregulated in combination with PI3 K family inhibitors (LY294002, wortmannin, PI-103, and 3-methyladenine). In addition, ROS generation was included in downstream signaling events associated with the phosphorylation of mTOR, because pretreatment of cells with rapamycin inhibited ROS generation. Conclusion: These results suggest that SeMet-induced apoptosis is affected by the Akt/mTOR/ROS pathway in A549 cells. Akt serves an anti-survival function in the system of SeMet-treated lung cancer cells, but autophagic signaling remained unsolved.
AB - Purpose: Although selenium compounds possess chemotherapeutic features by inducing apoptosis in cancer cells with trivial side effects on normal cells, the mechanisms underlying its anti-cancer activity are insufficiently understood at the present. In this study, we investigated the effects of rapamycin on apoptosis induced by seleno-L-methionine (SeMet) or selenite in A549 cells. Methods: The effects of Se compounds, SeMet and selenite, on cell proliferation, apoptosis and its signaling pathway were investigated in established human adenocarcinoma cell line (A549). Cancer cells were treated with each Se during different periods. Cell apoptosis and signaling molecules were analyzed by flow cytometry (TUNEL method) or immunoblotting, respectively. Results: SeMet induces reactive oxygen species generation associated with the induction of apoptosis, because pretreatment of cells with N-acetyl-L-cysteine completely blocked SeMet-induced apoptosis. We also found that rapamycin completely suppressed the apoptosis of cells treated by SeMet, but not selenite. SeMet-induced apoptosis is significantly downregulated in combination with PI3 K family inhibitors (LY294002, wortmannin, PI-103, and 3-methyladenine). In addition, ROS generation was included in downstream signaling events associated with the phosphorylation of mTOR, because pretreatment of cells with rapamycin inhibited ROS generation. Conclusion: These results suggest that SeMet-induced apoptosis is affected by the Akt/mTOR/ROS pathway in A549 cells. Akt serves an anti-survival function in the system of SeMet-treated lung cancer cells, but autophagic signaling remained unsolved.
KW - Akt/mTOR
KW - Apoptosis
KW - ROS
KW - Rapamycin
KW - Selenite
KW - Seleno-L-methionine
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U2 - 10.1007/s00280-010-1417-7
DO - 10.1007/s00280-010-1417-7
M3 - Article
C2 - 20680277
AN - SCOPUS:79955568265
SN - 0344-5704
VL - 67
SP - 1129
EP - 1136
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 5
ER -