Inhibition of Akt (ser473) Phosphorylation and Rapamycin-Resistant Cell Growth by Knockdown of Mammalian Target of Rapamycin with Small Interfering RNA in Vascular Endothelial Growth Factor Receptor-1-Targeting Vector
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概要
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Previously we developed dicetyl phosphate-tetraethylenepentamine-based polycation liposomes (TEPA-PCL) for use in small interfering RNA (siRNA) therapy. In the present study, mammalian target of rapamycin (mTOR) expression in cancer cells was silenced with mTOR-siRNA (simTOR) formulated in TEPA-PCL modified with Ala-Pro-Arg-Pro-Gly (APRPG), a peptide having affinity for vascular endothelial growth factor receptor-1 (VEGFR-1). We investigated the effects of inhibition of mTOR, focusing on the differences between cells treated with simTOR and those with rapamycin in terms of Akt (ser473) phosphorylation and antiproliferative effects. Rapamycin treatment is known to induce Akt (ser473) phosphorylation which attenuates the antiproliferative effects of rapamycin. As a result, knockdown of mTOR did not alter or only slightly reduced Akt (ser473) phosphorylation in phosphatase and tensin homolog deleted from chromosome 10 (PTEN)-null (LNCaP and MDA-MB-468 cells) and PTEN-positive (DU 145 and MDA-MB-231) cells, although rapamycin induced Akt (ser473) phosphorylation of these cells. Rapamycin suppressed the growth of PTEN-null cells, in which the rapamycin-sensitive mTOR complex 1 (mTORC1) is excessively activated. On the other hand, rapamycin did not suppress the growth of PTEN-positive cells possibly through a negative feedback mechanism via the rapamycin-insensitive mTOR complex 2 (mTORC2) signaling pathway. In contrast, simTOR significantly suppressed the growth of cancer cells regardless of the presence of PTEN, possibly through inhibition of both mTORC1 and mTORC2. These results indicate that mTOR knockdown using APRPG-TEPA-PCL/simTOR is likely to be an effective strategy for cancer siRNA therapy.
著者
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Nango Mamoru
Materials Science And Engineering Nagoya Institute Of Technology
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ASAI Tomohiro
Department of Cardiovascular Surgery, Okayama University Graduate School of Medicine, Dentistry, and
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OKU Naoto
Department of Radiobiochemistry, School of Pharmaceutical Sciences, University of Shizuoka
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FURUYA Keiichi
Department of Applied Chemistry, Faculty of Science, Science University of Tokyo
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KATO HIROKI
Department of Tumor and General Surgery, Gifu University School of Medicine
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Oku Naoto
Department Of Medical Biochemistry And Coe Program In The 21st Century University Of Shizuoka School
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Asai Tomohiro
Department Of Medical Biochemistry And Global Coe University Of Shizuoka School Of Pharmaceutical Sc
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Asai T
Department Of Medical Biochemistry And Coe Program In The 21st Century University Of Shizuoka School
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Asai Tomohiro
Department Of Cardiovascular Surgery Okayama University Graduate School Of Medicine Dentistry And Ph
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Furuya Keiichi
Department Of Applied Chemistry Faculty Of Science Science University Of Tokyo
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Asai Tomohiro
Department Of Medical Biochemistry University Of Shizuoka School Of Pharmaceutical Sciences
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Dewa Takehisa
Materials Science And Engineering Nagoya Institute Of Technology
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Koide Hiroyuki
Department of Medical Biochemistry and Global COE Program, Graduate School of Pharmaceutical Science
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Tsuzuku Takuma
Department of Medical Biochemistry and Global COE Program, Graduate School of Pharmaceutical Science
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Maeda Noriyuki
Nippon Fine Chemical Co., Ltd.
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Kato Hiroki
Department Of Crystalline Materials Science School Of Engineering Nagoya University
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Kato Hiroki
Department Of Cardiovascular Surgery Hokkaido University Hospital
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Asai Tomohiro
Department of Medical Biochemistry and Global COE Program, Graduate School of Pharmaceutical Sciences, University of Shizuoka
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KATO Hiroki
Department of Applied Chemistry, Faculty of Science, Science University of Tokyo
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Kato Hiroki
Department of Medical Biochemistry and Global COE Program, Graduate School of Pharmaceutical Sciences, University of Shizuoka
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Nango Mamoru
Materials Science and Engineering, Nagoya Institute of Technology
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Koide Hiroyuki
Department of Medical Biochemistry and Global COE Program, Graduate School of Pharmaceutical Sciences, University of Shizuoka
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Oku Naoto
Department of Medical Biochemistry and Global COE Program, Graduate School of Pharmaceutical Sciences, University of Shizuoka
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Tsuzuku Takuma
Department of Medical Biochemistry and Global COE Program, Graduate School of Pharmaceutical Sciences, University of Shizuoka
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Dewa Takehisa
Materials Science and Engineering, Nagoya Institute of Technology
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Furuya Keiichi
Department of Medical Biochemistry and Global COE Program, Graduate School of Pharmaceutical Sciences, University of Shizuoka
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OKU Naoto
Department of Biochemistry, Faculty of Pharmaceutical Sciences, Setsunan University
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