Acquisition of resistance to trastuzumab in gastric cancer cells is associated with activation of IL-6/STAT3/Jagged-1/Notch positive feedback loop.
Acquisition of resistance to trastuzumab in gastric cancer cells is associated with activation of IL-6/STAT3/Jagged-1/Notch positive feedback loop.
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胃癌细胞对曲妥珠单抗耐药的获得与 IL-6/STAT3/Jagged-1/Notch 正反馈环的激活相关
DOI：
10.18632/oncotarget.3241
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发表时间：
2015-03-10
期刊：
影响因子：
--
通讯作者：
Shi M
中科院分区：
文献类型：
--
作者：
Yang Z;Guo L;Liu D;Sun L;Chen H;Deng Q;Liu Y;Yu M;Ma Y;Guo N;Shi M
在本研究中，我们证明曲妥珠单抗的长期治疗可诱导NCI - N87胃癌细胞对曲妥珠单抗产生耐药性。耐药细胞具有上皮 - 间质转化（EMT）/癌症干细胞的典型特征，并且在体外和体内都获得了更强的侵袭和转移潜能。曲妥珠单抗的长期治疗显著抑制了Akt的磷酸化，但引发了STAT3的激活。白细胞介素 - 6（IL - 6）的水平显著升高，这意味着驱动STAT3激活的IL - 6的释放启动了生存信号转导。此外，耐药细胞中的Notch活性显著增强，同时Notch配体Jagged - 1以及Notch应答基因Hey1和Hey2上调。抑制内源性Notch通路可降低IL - 6的表达，并恢复耐药细胞对曲妥珠单抗的敏感性。阻断STAT3信号可消除IL - 6诱导的Jagged - 1表达，有效抑制曲妥珠单抗耐药细胞的生长，并增强曲妥珠单抗在耐药细胞中的抗肿瘤活性。这些发现表明IL - 6/STAT3/Jagged - 1/Notch轴可能是一个有用的靶点，并且Notch或STAT3抑制剂与曲妥珠单抗联合使用可能预防或延缓临床耐药性，并提高曲妥珠单抗在胃癌中的疗效。
In the present study, we demonstrate that prolonged treatment by trastuzumab induced resistance of NCI-N87 gastric cancer cells to trastuzumab. The resistant cells possessed typical characteristics of epithelial to mesenchymal transition (EMT)/cancer stem cells and acquired more invasive and metastatic potentials both in vitro and in vivo. Long term treatment with trastuzumab dramatically inhibited the phosphorylation of Akt, but triggered the activation of STAT3. The level of IL-6 was remarkably increased, implicating that the release of IL-6 that drives the STAT3 activation initiates the survival signaling transition. Furthermore, the Notch activities were significantly enhanced in the resistant cells, companied by upregulation of the Notch ligand Jagged-1 and the Notch responsive genes Hey1 and Hey2. Inhibiting the endogenous Notch pathway reduced the IL-6 expression and restored the sensitivities of the resistant cells to trastuzumab. Blocking of the STAT3 signaling abrogated IL-6-induced Jagged-1 expression, effectively inhibited the growth of the trastuzumab resistant cells, and enhanced the anti-tumor activities of trastuzumab in the resistant cells. These findings implicate that the IL-6/STAT3/Jagged-1/Notch axis may be a useful target and that combination of the Notch or STAT3 inhibitors with trastuzumab may prevent or delay clinical resistance and improve the efficacy of trastuzumab in gastric cancer.
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影响因子：
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