Kazinol-E is a specific inhibitor of ERK that suppresses the enrichment of a breast cancer stem-like cell population
Kazinol-E is a specific inhibitor of ERK that suppresses the enrichment of a breast cancer stem-like cell population
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DOI：
10.1016/j.bbrc.2016.01.066
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发表时间：
2016-02-05
影响因子：
3.1
通讯作者：
Kim, Woo-Young
中科院分区：
文献类型：
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作者：
Jung, Yu-Chae;Han, Seula;Kim, Woo-Young
越来越多的证据表明，癌症干细胞（CSLCs）有助于乳腺癌的复发和对常规治疗的抵抗。细胞外信号调节激酶（ERIC）信号通路是控制多种细胞过程的主要决定因素，包括CSLCs的维持。在这项研究中，我们发现Kazinol-E，一种来自Broussonetia kazinoki的抗氧化黄酮类化合物，可以降低乳腺癌细胞系MCF7的CSLC数量。以CD44高/CD24低表达或醛脱氢酶1高活性为特征的CSLC群体被Kazinol-E浓度降低，但不影响MCF7细胞的生长。Kazinol-E不降低egf诱导的CSLCs中ERIC磷酸化，但确实阻断了ERK底物p90RSK2在Thr359/Ser363位点的磷酸化。我们进一步证明，在表达k - ras的野生型非小细胞肺癌细胞系H226B中，egf诱导的ERK活性被Kazinol-E阻断。以纯化的ERK1和p90RSK2为底物的体外激酶实验表明，Kazinol e可以直接抑制ERK活性。此外，分子对接研究提供了Kazinol- e与ERK1 ATP结合袋的推测结合模式，这些结果表明Kazinol- e是ERK1的直接抑制剂，需要更多的研究来开发该试剂用于治疗乳腺癌CSLC靶向。(C) 2016 Elsevier Inc.版权所有。
Growing evidence shows that cancer stem-like cells (CSLCs) contribute to breast cancer recurrence and to its resistance to conventional therapies. The extracellular signal-regulated kinase (ERIC) signaling pathway is a major determinant in the control of diverse cellular processes, including the maintenance of CSLCs. In this study, we found that Kazinol-E, an antioxidant flavan from Broussonetia kazinoki, decreased the CSLC population of a breast cancer cell line, MCF7. The CSLC population, characterized by CD44 high/CD24 low expression or by high Aldehyde dehydrogenase 1 activity, was decreased by a concentration of Kazinol-E that did not affect the growth of bulk-cultured MCF7 cells. Kazinol-E did not decrease EGF-induced ERIC phosphorylation in CSLCs, but did block the phosphorylation of an ERK substrate, p90RSK2, at Thr359/Ser363. We further demonstrated that EGF-induced ERK activity was blocked by Kazinol-E in a wild-type K-Ras-expressing non-small cell lung cancer cell line H226B. An in vitro kinase assay with purified ERK1 and p90RSK2 as its substrate demonstrated a direct inhibition of ERK activity by Kazinol E. Additionally, a the molecular docking study provided putative binding modes of Kazinol-E into the ATP binding pocket of ERK1 Collectively, these results suggest that Kazinol-E is a direct inhibitor of ERK1, and more studies are warranted to develop this reagent for therapeutic breast CSLC targeting. (C) 2016 Elsevier Inc. All rights reserved.