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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Zhengyan Yang1,*, Liang Guo1,*, Dan Liu1, Limin Sun1, Hongyu Chen1, Que Deng1, Yanjun Liu2, Ming Yu1, Yuanfang Ma2, Ning Guo1 and Ming Shi1
1 Institute of Basic Medical Sciences, Beijing, P.R. China
2 Laboratory of Cellular and Molecular Immunology, Medical School of Henan University, Kaifeng, P.R. China
* These authors contributed equally to this work
Ming Shi, email:
Ning Guo, email:
Keywords: trastuzumab, gastric cancer, STAT3, Notch
Received: September 29, 2014 Accepted: December 27, 2014 Published: December 31, 2014
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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