Key Laboratory of Digestive Pathophysiology of Zhejiang Province, the First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou 310006, China.
College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 310036, China.
J Zhejiang Univ Sci B. 2021 Jun 15;22(6):492-503. doi: 10.1631/jzus.B2000842.
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.
不同信号通路之间失调的串扰导致肿瘤的发展，包括对癌症治疗的耐药性。在本研究中，我们发现丝裂原活化的细胞外信号调节激酶 (MEK) 抑制剂曲美替尼通过激活 Janus 激酶 2 (JAK2)/信号转导和转录激活因子 3 (STAT3) 信号通路，未能抑制 PANC-1 和 MGC803 细胞的增殖，而 Jak2 抑制剂 fedratinib 未能抑制 ERK 信号刺激下 PANC-1 细胞的生长。特别是，Jak2/STAT3 和 ERK 信号通路的同时阻断产生了最显著的抗增殖作用增强。此外，两种抑制剂的联合使用导致小鼠肿瘤负担减轻。我们的证据表明胃癌 (GC) 和胰腺导管腺癌 (PDAC) 细胞中 JAK2/STAT3 和 ERK 信号之间存在新的串扰，并为克服胃肠道癌症的潜在耐药性提供了一种治疗策略。
