HER2 signaling downregulation by trastuzumab and suppression of the PI3K/Akt pathway:: An unexpected effect on TRAIL-induced apoptosis
HER2 signaling downregulation by trastuzumab and suppression of the PI3K/Akt pathway:: An unexpected effect on TRAIL-induced apoptosis
复制标题
DOI：
10.1016/j.febslet.2005.06.047
复制
发表时间：
2005-08-01
期刊：
影响因子：
3.5
通讯作者：
Sheard, MA
中科院分区：
文献类型：
--
作者：
Dubská, L;Andera, L;Sheard, MA
我们研究了曲妥珠单抗下调 HER2 是否会调节乳腺癌细胞对 TNF 相关凋亡诱导配体 (TRAIL) 的反应。有趣的是，与 SKBr3 细胞对 TRAIL 的反应增加相反，曲妥珠单抗降低了 BT474 细胞对 TRAIL 的敏感性。在外源抑制 P13-K/Akt 激酶（但不是 MAPK/ERK 激酶 (MEK)/丝裂原激活蛋白激酶 (MAPK)）后也观察到这种下降。在 BT474 细胞中，但在 SKBr3 细胞中，抑制 HER2/磷脂酰肌醇 3' 激酶 (PI3K)/Akt 通路会导致促凋亡受体 TRAIL 受体 1 (TRAIL-R1) 和 TRAIL-R2 下调。 TRAIL 诱导 caspase-8 激活、Bid 加工、AT 下降和多聚 ADP-核糖聚合酶 (PARP) 裂解，但不诱导 caspase-9 激活，这些事件在 HER2/PI3K/Akt 抑制的 BT474 细胞中受到抑制，另一方面，BT474 细胞表现出 BCl-X-L 下调和对丝裂霉素 C 的反应增加。 HER2/PI3K/Akt 通路可能通过诱导 TRAIL-R1 和 -R2 表达，从而增强对 TRAIL 的反应性，在某些细胞类型中发挥特定的促凋亡作用。 (c) 2005 年由 Elsevier B.V. 代表欧洲生化学会联合会出版。
We investigated whether HER2 downregulation by trastuzumab modulates the responsiveness of breast cancer cells to TNF-related apoptosis-inducing ligand (TRAIL). Interestingly, in contrast to increased response to TRAIL in SKBr3 cells, trastuzumab decreased the susceptibility of BT474 cells to TRAIL. This decrease was also observed after exogenous inhibition of P13-K/Akt kinase, but not MAPK/ERK kinase (MEK)/mitogen-activated protein kinase (MAPK). In BT474 cells, but not SKBr3 cells, inhibition of the HER2/phosphatidylinositol 3' kinase (PI3K)/Akt pathway resulted in downregulation of the pro-apoptotic receptors TRAIL-receptor 1 (TRAIL-R1) and TRAIL-R2. TRAIL-induced caspase-8 activation, Bid processing, drop of AT., and poly ADP-ribose polymerase (PARP) cleavage but not in caspase-9 activation, and these events were inhibited in HER2/PI3K/Akt-suppressed BT474 cells, which on the other hand exhibited downregulation of BCl-X-L and increased response to mitomycin C. We show that HER2/PI3K/Akt pathway may play a specific pro-apoptotic role in certain cell type by inducing TRAIL-R1 and -R2 expression and thereby enhancing responsiveness to TRAIL. (c) 2005 Published by Elsevier B.V. on behalf of the Federation of European Biochemical Societies.