Blocking the JAK2/STAT3 and ERK pathways suppresses the proliferation of gastrointestinal cancers by inducing apoptosis.

Xi Wang; Chunyan Dai; Yifei Yin; Lin WU; Weiyang Jin; Yufei FU; Zhe Chen; Ke Hao; Bin LU

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Blocking the JAK2/STAT3 and ERK pathways suppresses the proliferation of gastrointestinal cancers by inducing apoptosis.

Author: Xi WANG ¹ ; Chunyan DAI ¹ ; Yifei YIN ¹ ; Lin WU ² ; Weiyang JIN ² ; Yufei FU ¹ ; Zhe CHEN ¹ ; Ke HAO ³ ; Bin LU ¹
Author Information

1. Key Laboratory of Digestive Pathophysiology of Zhejiang Province, the First Affiliated Hospital of Zhejiang Chinese Medical University, Zhejiang Chinese Medical University, Hangzhou 310006, China.
2. College of Life and Environmental Sciences, Hangzhou Normal University, Hangzhou 310036, China.
3. Research Center of Blood Transfusion Medicine, Ministry of Education Key Laboratory of Laboratory Medicine, Department of Blood Transfusion, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, China.
Publication Type:Journal Article
Keywords: Apoptosis; Crosstalk; ERK pathway; Gastrointestinal cancers; JAK2/STAT3 pathway
From: Journal of Zhejiang University. Science. B 2021;22(6):492-503
CountryChina
Language:English
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.