| Ciclopirox olamine inhibits mTORC1 signaling by activation of AMPK | |
Zhou, Hongyu1,2,4; Shang, Chaowei2,3; Wang, Min1; Shen, Tao2,3; Kong, Lingmei1,4; Yu, Chunlei1,5; Ye, Zhennan1; Luo, Yan2; Liu, Lei2; Li, Yan1,4 ; Huang, Shile2,3
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| 2016-09-15 | |
| 发表期刊 | BIOCHEMICAL PHARMACOLOGY
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| 卷号 | 116页码:39-50 |
| 摘要 | Ciclopirox olamine (CPX), an off-patent antifungal agent, has recently been identified as a potential anticancer agent. The mammalian target of rapamycin (mTOR) is a central controller of cell growth, proliferation and survival. Little is known about whether and how CPX executes its anticancer action by inhibiting mTOR. Here we show that CPX inhibited the phosphorylation of p70 S6 kinase 1 (S6K1) and eukaryotic initiation factor 4E binding protein 1 (4E-BP1), two downstream effector molecules of mTOR complex 1 (mTORC1), in a spectrum of human tumor cells, indicating that CPX inhibits mTORC1 signaling. Using rhabdomyosarcoma cells as an experimental model, we found that expression of constitutively active mTOR (E2419K) conferred resistance to CPX inhibition of cell proliferation, suggesting that CPX inhibition of mTORC1 contributed to its anticancer effect. In line with this, treatment with CPX inhibited tumor growth and concurrently suppressed mTORC1 signaling in RD xenografts. Mechanistically, CPX inhibition of mTORC1 was neither via inhibition of IGF-I receptor or phosphoinositide 3-kinase (PI3K), nor by activation of phosphatase and tensin homolog (PTEN). Instead, CPX inhibition of mTORC1 was attributed to activation of AMP-activated protein kinase (AMPK)-tuberous sclerosis complexes (TSC)/raptor pathways. This is supported by the findings that CPX activated AMPK; inhibition of AMPK with Compound C or ectopic expression of dominant negative AMPK alpha partially prevented CPX from inhibiting mTORC1; silencing TSC2 attenuated CPX inhibition of mTORC1; and CPX also increased AMPK-mediated phosphorylation of raptor (S792). Therefore, the results indicate that CPX exerts the anticancer effect by activating AMPK, resulting in inhibition of mTORC1 signaling. (C) 2016 Elsevier Inc. All rights reserved. |
| 关键词 | Ciclopirox Mtor Ampk Tsc2 Raptor |
| DOI | 10.1016/j.bcp.2016.07.005 |
| 收录类别 | SCI |
| 语种 | 英语 |
| WOS记录号 | WOS:000383636500004 |
| 引用统计 | |
| 文献类型 | 期刊论文 |
| 条目标识符 | http://ir.kib.ac.cn/handle/151853/33574 |
| 专题 | 植物化学与西部植物资源持续利用国家重点实验室 |
| 作者单位 | 1.Chinese Acad Sci, Kunming Inst Bot, State Key Lab Phytochem & Plant Resources West Ch, Kunming 650201, Peoples R China 2.Louisiana State Univ, Hlth Sci Ctr, Dept Biochem & Mol Biol, Shreveport, LA 71130 USA 3.Louisiana State Univ, Hlth Sci Ctr, Feist Weiller Canc Ctr, Shreveport, LA 71130 USA 4.Chinese Acad Sci, Kunming Inst Bot, Yunnan Key Lab Nat Med Chem, Kunming 650201, Peoples R China 5.Univ Chinese Acad Sci, Beijing 100049, Peoples R China |
| 推荐引用方式 GB/T 7714 | Zhou, Hongyu,Shang, Chaowei,Wang, Min,et al. Ciclopirox olamine inhibits mTORC1 signaling by activation of AMPK[J]. BIOCHEMICAL PHARMACOLOGY,2016,116:39-50. |
| APA | Zhou, Hongyu.,Shang, Chaowei.,Wang, Min.,Shen, Tao.,Kong, Lingmei.,...&Huang, Shile.(2016).Ciclopirox olamine inhibits mTORC1 signaling by activation of AMPK.BIOCHEMICAL PHARMACOLOGY,116,39-50. |
| MLA | Zhou, Hongyu,et al."Ciclopirox olamine inhibits mTORC1 signaling by activation of AMPK".BIOCHEMICAL PHARMACOLOGY 116(2016):39-50. |
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