...
  • 主题
高级搜索  >
历史搜索 清空历史
首页> 外文期刊>The Korean Journal of Physiology & Pharmacology >Multiple Effects of a Novel Epothilone Analog on Cellular Processes and Signaling Pathways Regulated by Rac1 GTPase in the Human Breast Cancer Cells
【24h】

Multiple Effects of a Novel Epothilone Analog on Cellular Processes and Signaling Pathways Regulated by Rac1 GTPase in the Human Breast Cancer Cells

机译：新型埃坡霉素类似物对人乳腺癌细胞中Rac1 GTPase调控细胞过程和信号通路的多重影响

获取原文
           
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

The epothilones are a class of microtubule inhibitors that exhibit a strong antitumor activity. UTD2 is a novel epothilone analog generated by genetic manipulation of the polyketide biosynthetic gene cluster. This study investigated the effects of UTD2 on the actin cytoskeleton and its critical regulators, and the signaling pathways which are essential for cell motility, growth and survival in MCF-7 breast cancer cells. Results showed that UTD2 inhibited the cellular functions of actin cytoskeleton, such as wound-closure, migration and invasion, as well as adhesion. Our study further demonstrated that UTD2 suppressed Rac1 GTPase activation and reduced the activity of PAK1, which is a downstream effector of Rac1, while the activity of Cdc42 was not affected. Additionally, the phosphorylation of p38 and ERK were significantly inhibited, but the phosphorylation of JNK remained the same after UTD2 treatment. Moreover, UTD2 inhibited the activity and mRNA expression of MMP-2, which plays a key role in cell motility. UTD2 also reduced the phosphorylation of Akt, which is an important signaling kinase regulating the cell survival through Rac1. Furthermore, UTD2 interrupted the synergy between Rac1 and Raf in focus formation assays. Taken together, these results indicated that UTD2 exerted multiple effects on the actin cytoskeleton and signaling pathways associated with Rac1. This study provided novel insights into the molecular mechanism of the antineoplastic and antimetastatic activities of epothilones. Our findings also suggest that the signaling pathways regulated by Rac1 may be evaluated as biomarkers for the response to therapy in clinical trials of epothilones.
机译：埃坡霉素是一类显示出强大的抗肿瘤活性的微管抑制剂。 UTD2是通过对聚酮化合物生物合成基因簇进行遗传操作而产生的新型埃博霉素类似物。这项研究调查了UTD2对肌动蛋白细胞骨架及其关键调节剂的影响，以及对MCF-7乳腺癌细胞的细胞运动，生长和存活至关重要的信号通路。结果表明，UTD2抑制肌动蛋白细胞骨架的细胞功能，如伤口闭合，迁移和侵袭以及粘附。我们的研究进一步证明，UTD2抑制Rac1 GTPase的活化并降低PAK1的活性，而PAK1是Rac1的下游效应子，而Cdc42的活性未受影响。另外，p38和ERK的磷酸化被显着抑制，但是UTD2处理后JNK的磷酸化保持相同。此外，UTD2抑制MMP-2的活性和mRNA表达，这在细胞运动中起关键作用。 UTD2还减少了Akt的磷酸化，Akt是通过Rac1调节细胞存活的重要信号激酶。此外，在焦点形成试验中，UTD2中断了Rac1和Raf之间的协同作用。综上所述，这些结果表明UTD2对肌动蛋白的细胞骨架和与Rac1相关的信号传导途径具有多种作用。这项研究为埃博霉素的抗肿瘤和抗转移活性的分子机制提供了新的见解。我们的发现还表明，在Epothilones的临床试验中，Rac1调节的信号通路可能被评估为对治疗反应的生物标志物。

著录项

相似文献

  • 外文文献
  • 中文文献
  • 专利
获取原文

客服邮箱：kefu@zhangqiaokeyan.com

京公网安备：11010802029741号 ICP备案号：京ICP备15016152号-6 六维联合信息科技 (北京) 有限公司©版权所有

  • 客服微信

  • 服务号