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Rapamycin suppresses ROS-dependent apoptosis caused by selenomethionine in A549 lung carcinoma cells

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Abstract

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.

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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.

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Authors and Affiliations

  1. Department of Microbiology and Immunology, Tohoku University Graduate School of Dentistry, 4-1 Seiryo-machi, Aoba-ku, Sendai, 980-8575, Japan

    Maiko Suzuki, Manabu Endo & Hidemi Rikiishi

  2. Department of Oral Surgery, Tohoku University Graduate School of Dentistry, Sendai, 980-8575, Japan

    Manabu Endo, Fumiaki Shinohara & Seishi Echigo

Authors
  1. Maiko Suzuki
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  2. Manabu Endo
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  3. Fumiaki Shinohara
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  4. Seishi Echigo
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  5. Hidemi Rikiishi
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Correspondence to Hidemi Rikiishi.

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Suzuki, M., Endo, M., Shinohara, F. et al. Rapamycin suppresses ROS-dependent apoptosis caused by selenomethionine in A549 lung carcinoma cells. Cancer Chemother Pharmacol 67, 1129–1136 (2011). https://doi.org/10.1007/s00280-010-1417-7

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  • DOI: https://doi.org/10.1007/s00280-010-1417-7

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