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
| Autor: | Keiichi Furuya, Hiroki Kato, Mamoru Nango, Takehisa Dewa, Hiroyuki Koide, Takuma Tsuzuku, Naoto Oku, Tomohiro Asai, Noriyuki Maeda |
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| Rok vydání: | 2011 |
| Předmět: |
Small interfering RNA
Blotting Western Pharmaceutical Science mTORC1 Biology mTORC2 Cell Line Tumor Serine Humans PTEN Phosphorylation RNA Small Interfering Protein kinase B PI3K/AKT/mTOR pathway Pharmacology Vascular Endothelial Growth Factor Receptor-1 Base Sequence TOR Serine-Threonine Kinases RPTOR PTEN Phosphohydrolase General Medicine Gene Knockdown Techniques Cancer research biology.protein Proto-Oncogene Proteins c-akt Cell Division |
| Zdroj: | Biological and Pharmaceutical Bulletin. 34:602-608 |
| ISSN: | 1347-5215 0918-6158 |
| DOI: | 10.1248/bpb.34.602 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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