1. Blocking the JAK2/STAT3 and ERK pathways suppresses the proliferation of gastrointestinal cancers by inducing apoptosis.
- Author
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Wang X, Dai C, Yin Y, Wu L, Jin W, Fu Y, Chen Z, Hao K, and Lu B
- Subjects
- Animals, Cell Line, Tumor, Cell Proliferation, Extracellular Signal-Regulated MAP Kinases physiology, Female, Gastrointestinal Neoplasms pathology, Humans, Janus Kinase 2 physiology, Mice, Mice, Inbred BALB C, Pyridones therapeutic use, Pyrimidinones therapeutic use, Pyrrolidines therapeutic use, STAT3 Transcription Factor physiology, Signal Transduction drug effects, Sulfonamides therapeutic use, Tumor Microenvironment, Apoptosis drug effects, Extracellular Signal-Regulated MAP Kinases antagonists & inhibitors, Gastrointestinal Neoplasms drug therapy, Janus Kinase 2 antagonists & inhibitors, Protein Kinase Inhibitors therapeutic use, STAT3 Transcription Factor antagonists & inhibitors
- 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.
- Published
- 2021
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