Abstract
Dysregulated crosstalk between different signaling pathways contributes to tumor development, including resistance to cancer therapy. In the present study, we found that the mitogen-activated extracellular signal-regulated kinase (MEK) inhibitor trametinib failed to suppress the proliferation of PANC-1 and MGC803 cells by activating the Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) signaling pathway, while the JAK2 inhibitor fedratinib failed to inhibit the growth of the PANC-1 cells upon stimulation of extracellular signal-regulated kinase (ERK) signaling. In particular, the most prominent enhancement of the anti-proliferative effect resulted from the concurrent blockage of the JAK2/STAT3 and ERK signaling pathways. Furthermore, the combination of the two inhibitors resulted in a reduced tumor burden in mice. Our evidence suggests novel crosstalk between JAK2/STAT3 and ERK signaling in gastric cancer (GC) and pancreatic ductal adenocarcinoma (PDAC) cells and provides a therapeutic strategy to overcome potential resistance in gastrointestinal cancer.
Abstract
目的
探索在胃肠道肿瘤细胞中的JAK2/STAT3和MEK/ERK信号通路之间的交互作用, 明确两者相互作用在肿瘤细胞增殖和凋亡的作用。
创新点
发现JAK2/STAT3和ERK信号在胃癌 (GC) 和胰腺导管腺癌 (PDAC) 细胞内的相互作用, 为克服胃肠道肿瘤的化疗耐药提供新的治疗策略。
方法
在GC和PDAC细胞系中, 应用MEK抑制剂——曲美替尼 (Trametinib) 和JAK2抑制剂——费德拉替尼 (Fedratinib) 单独或共同抑制MEK和JAK2/STAT3信号通路, 利用CCK-8和蛋白质印迹 (western blot) 方法检测细胞增殖和凋亡, 及相关信号通路的激活情况; 同时利用荷瘤小鼠检测JAK2/STAT3和MEK信号通路的抑制对肿瘤生长的影响。
结论
本研究发现, MEK抑制剂——曲美替尼在抑制MEK信号通路的同时却对JAK2/STAT3信号通路有较强的激活作用, 无法有效抑制胃癌细胞和胰腺癌细胞的增殖; 而JAK2抑制剂——费德拉替尼虽可以有效抑制JAK/STAT3信号通路的激活, 但显著促进ERK信号通路的异常活化, 导致对胃癌细胞和胰腺癌细胞的生长抑制作用失效。而当JAK2/STAT3和ERK信号通路同时被抑制后, 抗增殖效果显著增强, 且该作用效应与促进肿瘤细胞的凋亡进程密切相关。此外, 这两种抑制剂的结合有效阻止了荷瘤小鼠的肿瘤生长, 有很好的抗肿瘤效果, 避免了化疗耐药的发生。
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Acknowledgments
This study was supported by the Zhejiang Provincial Natural Science Foundation of China (Nos. LQ18H280005 and LY21H030002), the National Natural Science Foundation of China (Nos. 81770535, 81600595, 81503297, 81603340, 81773945, and 81803775), the Medical Health Science and Technology Project of Zhejiang Provincial Health Commission (Nos. 2019RC228, 2019RC229, and 2019RC113), and the Open Foundation from Chinese and Western Integrative Medicine in the Most Important Subjects of Zhejiang (No. ZXYJH2018002), China.
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Xi WANG, Chunyan DAI, Yifei YIN, and Yufei FU performed the experimental research and data analysis. Xi WANG, Chunyan DAI, and Zhe CHEN wrote and edited the manuscript. Lin WU and Weiyang JIN performed the establishment of animal models. Ke HAO and Bin LU contributed to the study design, data analysis, writing and editing of the manuscript. All authors have read and approved the final manuscript and, therefore, have full access to all the data in the study and take responsibility for the integrity and security of the data.
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Xi WANG, Chunyan DAI, Yifei YIN, Lin WU, Weiyang JIN, Yufei FU, Zhe CHEN, Ke HAO, and Bin LU declare that they have no conflict of interest.
All institutional and national guidelines for the care and use of laboratory animals were followed. Approval for the animal experiments was obtained from the Experimental Animal Committee of the Provincial Government of Zhejiang (China), and the animal protocols fulfilled the institutional guidelines on the Protection of Animals used for Scientific or Educational Purposes.
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Wang, X., Dai, C., Yin, Y. et al. Blocking the JAK2/STAT3 and ERK pathways suppresses the proliferation of gastrointestinal cancers by inducing apoptosis. J. Zhejiang Univ. Sci. B 22, 492–503 (2021). https://doi.org/10.1631/jzus.B2000842
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DOI: https://doi.org/10.1631/jzus.B2000842