Combination of MEK Inhibitor and the JAK2-STAT3 Pathway Inhibition for the Therapy of Colon Cancer
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The study aimed to investigate the reason of HCT116 cell resistance to MEK inhibitor, and the combination treatment effects of MEK inhibitor AZD6244 and JAK2/STAT3 inhibitor AG490 on colon cancer in vitro and in vivo, including cell viability, apoptosis, and explore the partial mechanisms focused on AZD6244 promoted the activation of JAK2-STAT3 pathways. In vitro, we examined the HCT116 cell viability by CCK8, cell apoptosis by flow cytometry; Western blot measured p-ERK, p-JAK2, p-STAT3 and STAT3 expression. In vivo, nude mice were subcutaneously injected by HCT116 cells. The tumor volume and weight were detected. HCT116 cell resistance to MEK inhibitor AZD6244, which inhibited the activation of ERK and promoted the activation of JAK2-STAT3 signaling. The combination treatment of AZD6244 and AG490 significantly inhibited cell viability and induced cell apoptosis, and completely inhibited the activation of ERK and JAK2-STAT3 signaling. Combination treatment of AZD6244 and AG490 had a stronger effect than that of AZD6244 as a monotherapy in vitro and in vivo. The treatment of AZD6244 on K-Ras mutations HCT116 cells promoted the activation of JAK2/STAT3 signaling. JAK2/STAT3 inhibitor AG490 synergistically increases effects of AZD6244 on colon cancer in vitro and in vivo. Collectively, these results provide a rationale for combining inhibitors of the JAK/STAT pathway and MEK inhibitors to reduce the potential impact of drug resistance.
KeywordsMEK inhibitors Colon cancer JAK2 STAT3
This work was financially supported by Taizhou Science and Technology Planning Project (2016A33170).
Yanan zhu contributed to the design of the study, served as the study coordinator, and helped to review the manuscript. Jianying Jin designed the study, performed experiments, collected data and wrote the manuscript. Qunyi Guo, Jingjing Xie, Dan Jin helped perform experiments and interpret data. All authors read and approved the final manuscript.
Compliance with Ethical Standards
Conflict of Interest
The authors report no conflict of interest. The authors alone are responsible for the content and writing of this article.
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