PIM Kinase Inhibitors Downregulate STAT3(Tyr705) Phosphorylation
文献类型：期刊论文
| 作者 | CHANG MARISA ; KANWAR NISHA ; FENG ERIC ; SIU ALLAN ; Liu XJ(刘秀洁) ; Ma DW(马大为) ; JONGSTRA JAN |
| 刊名 | Mol. Cancer Ther.
 |
| 出版日期 | 2010 |
| 卷号 | 9期号:9页码:2478-2487 |
| ISSN号 | 1535-7163 |
| 其他题名 | PIM激酶抑制剂STAT3Tyr705 |
| 通讯作者 | JONGSTRA JAN |
| 英文摘要 | Using a cell-based high-throughput screen designed to detect small chemical compounds that inhibit cell growth and survival, we identified three structurally related compounds, 21A8, 21H7, and 65D4, with differential activity on cancer versus normal cells. Introduction of structural modifications yielded compound M-110, which inhibits the proliferation of prostate cancer cell lines with IC(50)s of 0.6 to 0.9 mu mol/L, with no activity on normal human peripheral blood mononuclear cells up to 40 mu mol/L. Screening of 261 recombinant kinases and subsequent analysis revealed that M-110 is a selective inhibitor of the PIM kinase family, with preference for PIM-3. The prostate cancer cell line DU-145 and the pancreatic cancer cell line MiaPaCa2 constitutively express activated STAT3 (pSTAT3(Tyr705)). Treatment of DU-145 cells with M-110 or with a structurally unrelated PIM inhibitor, SGI-1776, significantly reduces pSTAT3(Tyr705) expression without affecting the expression of STAT3. Furthermore, treatment of DU-145 cells with M-110 attenuates the interleukin-6-induced increase in pSTAT3(Tyr705). To determine which of the three PIM kinases is most likely to inhibit expression of pSTAT3(Tyr705), we used PIM-1-, PIM-2-, or PIM-3-specific siRNA and showed that knockdown of PIM-3, but not of PIM-1 or PIM-2, in DU-145 cells results in a significant downregulation of pSTAT3(Tyr705). The phosphorylation of STAT5 on Tyr694 in 22Rv1 cells is not affected by M-110 or SGI-1776, suggesting specificity for pSTAT3(Tyr705). These results identify a novel role for PIM-3 kinase as a positive regulator of STAT3 signaling and suggest that PIM-3 inhibitors cause growth inhibition of cancer cells by downregulating the expression of pSTAT3(Tyr705). Mol Cancer Ther; 9(9); 2478-87. (C) 2010 AACR. |
| 学科主题 | 生命有机化学 |
| 收录类别 | SCI |
| 原文出处 | http://dx.doi.org/10.1158/1535-7163.MCT-10-0321 |
| 语种 | 英语 |
| WOS记录号 | WOS:000281683000005 |
| 公开日期 | 2013-02-19 |
| 源URL | [http://202.127.28.38/handle/331003/15627]  |
| 专题 | 上海有机化学研究所_生命有机化学国家重点实验室 |
| 推荐引用方式 GB/T 7714 | CHANG MARISA,KANWAR NISHA,FENG ERIC,et al. PIM Kinase Inhibitors Downregulate STAT3(Tyr705) Phosphorylation[J]. Mol. Cancer Ther.,2010,9(9):2478-2487. |
| APA | CHANG MARISA.,KANWAR NISHA.,FENG ERIC.,SIU ALLAN.,刘秀洁.,...&JONGSTRA JAN.(2010).PIM Kinase Inhibitors Downregulate STAT3(Tyr705) Phosphorylation.Mol. Cancer Ther.,9(9),2478-2487. |
| MLA | CHANG MARISA,et al."PIM Kinase Inhibitors Downregulate STAT3(Tyr705) Phosphorylation".Mol. Cancer Ther. 9.9(2010):2478-2487. |
入库方式： OAI收割
来源：上海有机化学研究所
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