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Sertraline, a selective serotonin reuptake inhibitor, is a widely used antidepressant agent. Here, we show that sertraline also exhibits antiproliferative activity. Exposure to sertraline leads to a concentration-dependent decrease in protein synthesis. Moreover, polysome profile analysis of sertraline-treated cells shows a reduction in polysome content and a concomitant increase in 80S ribosomes. The inhibition in translation caused by sertraline is associated with decreased levels of the eukaryotic initiation factor (eIF) 4F complex, altered localization of eIF4E, and increased eIF2α phosphorylation. The latter event leads to increased REDD1 expression, which in turn impinges on the mammalian target of rapamycin (mTOR) pathway by affecting TSC1/2 signaling. Sertraline also independently targets the mTOR signaling pathway downstream of Rheb. In the Eμ-myc murine lymphoma model where carcinogenesis is driven by phosphatase and tensin homologue (PTEN) inactivation, sertraline is able to enhance chemosensitivity to doxorubicin. Our results indicate that sertraline exerts antiproliferative activity by targeting the mTOR signaling pathway in a REDD1-dependent manner. Cancer Res; 70(8); 3199–208. ©2010 AACR.

Supplementary Figure 1 from The Antidepressant Sertraline Inhibits Translation Initiation by Curtailing Mammalian Target of Rapamycin Signaling

Supplementary Figure 5 from The Antidepressant Sertraline Inhibits Translation Initiation by Curtailing Mammalian Target of Rapamycin Signaling

Supplementary Figure 3 from The Antidepressant Sertraline Inhibits Translation Initiation by Curtailing Mammalian Target of Rapamycin Signaling

Supplementary Figure 2 from The Antidepressant Sertraline Inhibits Translation Initiation by Curtailing Mammalian Target of Rapamycin Signaling

Supplementary Figure 4 from The Antidepressant Sertraline Inhibits Translation Initiation by Curtailing Mammalian Target of Rapamycin Signaling

The Alliance for Cellular Signaling is a large-scale collaboration designed to answer global questions about signalling networks. Pathways will be studied intensively in two cells — B lymphocytes (the cells of the immune system) and cardiac myocytes — to facilitate quantitative modelling. One goal is to catalyse complementary research in individual laboratories; to facilitate this, all alliance data are freely available for use by the entire research community.

この博士論文全文の閲覧方法については、以下のサイトをご参照ください。, https://www.lib.hokudai.ac.jp/dissertations/copy-guides/, (主査) 教授 村上 洋太, 教授 坂口 和靖, 教授 大利 徹, 教授 石森 浩一郎, 教授 Stephen Michnick（モントリオール大学）, 教授 James G. Omichinski（モントリオール大学）, 教授 坂本 寛（九州工業大学）, 総合化学院（総合化学専攻）

(主査) 教授 村上 洋太, 教授 坂口 和靖, 教授 大利 徹, 教授 石森 浩一郎, 教授 Stephen Michnick（モントリオール大学）, 教授 James G. Omichinski（モントリオール大学）, 教授 坂本 寛（九州工業大学）, 総合化学院（総合化学専攻）