title: Acquisition of resistance to trastuzumab in gastric cancer cells is associated with activation of IL-6/STAT3/Jagged-1/Notch positive feedback loop.
abstract: 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.
authors: Institute of Basic Medical Sciences, Beijing, P.R. China.
authors: Zhengyan
authors: Z
authors: Yang
authors: Institute of Basic Medical Sciences, Beijing, P.R. China.
authors: Liang
authors: L
authors: Guo
authors: Institute of Basic Medical Sciences, Beijing, P.R. China.
authors: Dan
authors: D
authors: Liu
authors: Institute of Basic Medical Sciences, Beijing, P.R. China.
authors: Limin
authors: L
authors: Sun
authors: Institute of Basic Medical Sciences, Beijing, P.R. China.
authors: Hongyu
authors: H
authors: Chen
authors: Institute of Basic Medical Sciences, Beijing, P.R. China.
authors: Que
authors: Q
authors: Deng
authors: Laboratory of Cellular and Molecular Immunology, Medical School of Henan University, Kaifeng, P.R. China.
authors: Yanjun
authors: Y
authors: Liu
authors: Institute of Basic Medical Sciences, Beijing, P.R. China.
authors: Ming
authors: M
authors: Yu
authors: Laboratory of Cellular and Molecular Immunology, Medical School of Henan University, Kaifeng, P.R. China.
authors: Yuanfang
authors: Y
authors: Ma
authors: Institute of Basic Medical Sciences, Beijing, P.R. China.
authors: Ning
authors: N
authors: Guo
authors: Institute of Basic Medical Sciences, Beijing, P.R. China.
authors: Ming
authors: M
authors: Shi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002135:Calcium-Binding Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D000072100:Jagged-1 Protein; D008297:Male; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D010766:Phosphorylation; D011897:Random Allocation; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000072099:Serrate-Jagged Proteins; D015398:Signal Transduction; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D000068878:Trastuzumab / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D002135:Calcium-Binding Proteins; C508600:IL6 protein, human; D036341:Intercellular Signaling Peptides and Proteins; D015850:Interleukin-6; C000606273:JAG1 protein, human; C000606274:Jag1 protein, mouse; D000072100:Jagged-1 Protein; D008565:Membrane Proteins; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D000072099:Serrate-Jagged Proteins; D000068878:Trastuzumab
keywords: Notch; STAT3; gastric cancer; trastuzumab