• 主题
高级搜索  >
历史搜索 清空历史
首页> 外文学位 >Crosstalk between the TGF-beta/Smad and PI3K/Akt pathways in the human epithelial MCF10A cell lineage and implications of signaling inhibitors.
【24h】

Crosstalk between the TGF-beta/Smad and PI3K/Akt pathways in the human epithelial MCF10A cell lineage and implications of signaling inhibitors.

机译：人上皮MCF10A细胞谱系中TGF-beta / Smad和PI3K / Akt通路之间的串扰和信号抑制剂的含义。

获取原文
获取原文并翻译 | 示例
页面导航
  • 摘要
  • 著录项
  • 相似文献
  • 相关主题

摘要

Breast cancer progression is a multiple-step process which results from complex signaling pathways associated with cell proliferation, cell survival, cell cycle regulation, apoptosis and epithelial-mesenchymal transition. The Ras, PI3K and Akt survival signaling pathway components are activated in the premalignant 10AT cells, and higher activation levels were observed in the CA1h and CA1a tumor cells. Ras levels were increased by 3.5-, 12.0-, and 9.8-fold in the 10AT, CA1h and CA1a cells, respectively, relative to the 10A cells. PI3K activity was elevated by 2.4- and 2.5-fold in the CA1h and CA1a cells, relative to 10A cells, respectively. CA1h and CA1a are having a low cell proliferation rate, resulting from the dysregulated cell cycle progression. CA1a cells are vulnerable to serum-starvation-induced apoptosis. E-cadherin, the epithelial marker of EMT, is decreased by &sim25.0% in the CA1a cells, whereas the mesenchymal marker vimentin levels increases by 1.8-, 1.9-, and 2.2-fold in the 10AT, CA1h and CA1a cells, respectively. These data suggest that differential alterations in signaling occur in Breast cancer progression is a multiple-step process which results from complex signaling pathways associated with cell proliferation, cell survival, cell cycle regulation, apoptosis and epithelial-mesenchymal transition. The Ras, PI3K and Akt survival signaling pathway components are activated in the premalignant 10AT cells, and higher activation levels were observed in the CA1h and CA1a tumor cells. Ras levels were increased by 3.5-, 12.0-, and 9.8-fold in the 10AT, CA1h and CA1a cells, respectively, relative to the 10A cells. PI3K activity was elevated by 2.4- and 2.5-fold in the CA1h and CA1a cells, relative to 10A cells, respectively. CA1h and CA1a are having a low cell proliferation rate, resulting from the dysregulated cell cycle progression. CA1a cells are vulnerable to serum-starvation-induced apoptosis. E-cadherin, the epithelial marker of EMT, is decreased by &sim25.0% in the CA1a cells, whereas the mesenchymal marker vimentin levels increases by 1.8-, 1.9-, and 2.2-fold in the 10AT, CA1h and CA1a cells, respectively. These data suggest that differential alterations in signaling occur in tumorigenesis and that tumor cells originating from the same progenitor cells exhibit differential and heterogeneous characteristics in key regulatory signaling components.TGF-beta is an inflammatory cytokine that has been demonstrated to be involved in breast cancer progression. Thus, the TGF-beta signaling in the MCF10A benign, premalignant and tumor human breast epithelial cell lineage has been examined. TGF-beta phosphorylates Smad2/3 equally in the 10A, 10AT, CA1h and CA1a cells. TGF-beta activation of Smad3 is mediated through TbetaRI. TGF-beta also activates PI3K/Akt/mTOR signaling pathway. TGF-beta increases PI3K activity by &sim2.3- and 2.5-fold in the 10A and 10AT cells, with no TGF-beta response in the CA1h and CA1a cells. TGF-beta increases Akt phosphorylation in the 10A and 10AT cells by &sim2.5- and 2.6-fold for Akt Ser473 and by &sim9.0- and 4.9-fold for Akt Thr308, respectively. TGF-beta increases mTOR phosphorylation by &sim2.3- and 2.4-fold in the 10A and 10AT cells, respectively. TGF-beta activation of PI3K, Akt and mTOR is mediated through Ras, rather than through TbetaRI. How TGF-beta activates Ras remains unclear. Interestingly, Ras is required for both the basal and TGF-beta-induced Smad3 phosphorylation through its downstream target mTOR, but not through PI3K or Akt.To get higher efficacy, combinational treatment is required. Thus, the combinational effects of Akt inhibitor and mTOR inhibitor on cell proliferation, survival and cell cycle have been examined. Akt inhibitor A-443654 induces apoptosis in a dose-dependent manner, with CA1a cells more sensitive than the 10A cells. Combination with rapamycin synergizes the apoptotic effects of A-443654, which results in increased efficacy in inducing apoptosis in CA1a cells, but are well-tolerated by the 10A cells.
机译：乳腺癌的进展是一个多步骤的过程，其起因于与细胞增殖，细胞存活，细胞周期调节，细胞凋亡和上皮-间质转化相关的复杂信号通路。 Ras，PI3K和Akt生存信号通路成分在恶变前10AT细胞中被激活，并且在CA1h和CA1a肿瘤细胞中观察到更高的激活水平。与10A细胞相比，10AT，​​CA1h和CA1a细胞的Ras水平分别提高了3.5倍，12.0和9.8倍。相对于10A细胞，CA1h和CA1a细胞的PI3K活性分别提高了2.4倍和2.5倍。由于细胞周期进程失调，CA1h和CA1a的细胞增殖率较低。 CA1a细胞易受血清饥饿诱导的凋亡的影响。 E-cadherin，EMT的上皮标记物，在CA1a细胞中下降了＆sim25.0％，而间质标记波形蛋白水平在10AT，​​CA1h和CA1a细胞中分别上升了1.8倍，1.9倍和2.2倍。 。这些数据表明，在乳腺癌进展中发生的信号差异变化是一个多步过程，其起因于与细胞增殖，细胞存活，细胞周期调节，细胞凋亡和上皮-间质转化相关的复杂信号通路。 Ras，PI3K和Akt生存信号通路成分在恶变前的10AT细胞中被激活，并且在CA1h和CA1a肿瘤细胞中观察到更高的激活水平。与10A细胞相比，10AT，​​CA1h和CA1a细胞的Ras水平分别提高了3.5倍，12.0和9.8倍。相对于10A细胞，CA1h和CA1a细胞的PI3K活性分别提高了2.4倍和2.5倍。由于细胞周期进程失调，CA1h和CA1a的细胞增殖率较低。 CA1a细胞易受血清饥饿诱导的凋亡的影响。 E-cadherin，EMT的上皮标记物，在CA1a细胞中下降了＆sim25.0％，而间质标记波形蛋白水平在10AT，​​CA1h和CA1a细胞中分别上升了1.8倍，1.9倍和2.2倍。 。这些数据表明，肿瘤发生中信号的差异发生变化，并且源自同一祖细胞的肿瘤细胞在关键调节信号成分中表现出差异性和异质性。TGF-β是一种炎症细胞因子，已被证明与乳腺癌的进展有关。 。因此，已经检查了MCF10A良性，恶变前和肿瘤人乳腺上皮细胞谱系中的TGF-β信号传导。 TGF-β在10A，10AT，​​CA1h和CA1a细胞中均等地磷酸化Smad2 / 3。 Smad3的TGF-β激活是通过TbetaRI介导的。 TGF-beta还激活PI3K / Akt / mTOR信号通路。 TGF-beta在10A和10AT细胞中使PI3K活性增加了＆sim2.3-和2.5-倍，而CA1h和CA1a细胞中没有TGF-beta响应。 TGF-beta对10A和10AT细胞的Akt磷酸化作用分别使Akt Ser473的＆sim2.5和2.6倍增加，对Akt Thr308的＆sim9.0和4.9倍增加。 TGF-β在10A和10AT细胞中分别使mTOR磷酸化增加＆sim2.3-和2.4-倍。 PI3K，Akt和mTOR的TGF-beta激活是通过Ras而不是通过TbetaRI介导的。尚不清楚TGF-beta如何激活Ras。有趣的是，基础和TGF-β诱导的Smad3磷酸化都需要通过其下游靶标mTOR而不是PI3K或Akt来实现Ras，为了获得更高的疗效，需要联合治疗。因此，已经检查了Akt抑制剂和mTOR抑制剂对细胞增殖，存活和细胞周期的组合作用。 Akt抑制剂A-443654以剂量依赖性方式诱导凋亡，CA1a细胞比10A细胞更敏感。与雷帕霉素的组合可增强A-443654的凋亡作用，从而增加诱导CA1a细胞凋亡的功效，但10A细胞具有很好的耐受性。

著录项

  • 作者

    Zheng, Jie.;

  • 作者单位

    Wayne State University.;

  • 授予单位 Wayne State University.;
  • 学科 Biology Molecular.Biology Cell.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 154 p.
  • 总页数 154
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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