Vortioxetine hydrobromide inhibits the growth of gastric cancer cells in vivo and in vitro by targeting JAK2 and SRC

Mingzhu Li; Lina Duan; Wenjie Wu; Wenjing Li; Lili Zhao; Ang Li; Xuebo Lu; Xinyu He; Zigang Dong; Kangdong Liu; Yanan Jiang

doi:10.1038/s41389-023-00472-4

Vortioxetine hydrobromide inhibits the growth of gastric cancer cells in vivo and in vitro by targeting JAK2 and SRC

Oncogenesis. 2023 May 5;12(1):24. doi: 10.1038/s41389-023-00472-4.

Authors

Mingzhu Li^#^{1

2}, Lina Duan^#^{1

2}, Wenjie Wu^{1

2}, Wenjing Li^{1

2}, Lili Zhao¹, Ang Li^{1

2}, Xuebo Lu^{1

2}, Xinyu He^{1

2}, Zigang Dong^{3

4}, Kangdong Liu^{5

6

7

8

9

10}, Yanan Jiang^{11

12

13}

Affiliations

¹ Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, 450000, China.
² China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, Henan, China.
³ Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, 450000, China. dongzg@zzu.edu.cn.
⁴ China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, Henan, China. dongzg@zzu.edu.cn.
⁵ Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, 450000, China. kdliu@zzu.edu.cn.
⁶ China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, Henan, China. kdliu@zzu.edu.cn.
⁷ State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, 450000, Henan, China. kdliu@zzu.edu.cn.
⁸ Provincial Cooperative Innovation Center for Cancer Chemoprevention, Zhengzhou University, Zhengzhou, 450000, Henan, China. kdliu@zzu.edu.cn.
⁹ Cancer Chemoprevention International Collaboration Laboratory, Zhengzhou, 450000, Henan, China. kdliu@zzu.edu.cn.
¹⁰ Center for Basic Medical Research, Zhengzhou University, Zhengzhou, 450000, Henan, China. kdliu@zzu.edu.cn.
¹¹ Department of Pathophysiology, School of Basic Medical Sciences, Academy of Medical Science, Zhengzhou University, Zhengzhou, 450000, China. yananjiang@zzu.edu.cn.
¹² China-US (Henan) Hormel Cancer Institute, Zhengzhou, 450000, Henan, China. yananjiang@zzu.edu.cn.
¹³ State Key Laboratory of Esophageal Cancer Prevention and Treatment, Zhengzhou, 450000, Henan, China. yananjiang@zzu.edu.cn.

^# Contributed equally.

Abstract

Gastric cancer is the fourth leading cause of cancer deaths worldwide. Most patients are diagnosed in the advanced stage. Inadequate therapeutic strategies and the high recurrence rate lead to the poor 5-year survival rate. Therefore, effective chemopreventive drugs for gastric cancer are urgently needed. Repurposing clinical drugs is an effective strategy for discovering cancer chemopreventive drugs. In this study, we find that vortioxetine hydrobromide, an FDA-approved drug, is a dual JAK2/SRC inhibitor, and has inhibitory effects on cell proliferation of gastric cancer. Computational docking analysis, pull-down assay, cellular thermal shift assay (CETSA) and in vitro kinase assays are used to illustrate vortioxetine hydrobromide directly binds to JAK2 and SRC kinases and inhibits their kinase activities. The results of non-reducing SDS-PAGE and Western blotting indicate that vortioxetine hydrobromide suppresses STAT3 dimerization and nuclear translocation activity. Furthermore, vortioxetine hydrobromide inhibits the cell proliferation dependent on JAK2 and SRC and suppresses the growth of gastric cancer PDX model in vivo. These data demonstrate that vortioxetine hydrobromide, as a novel dual JAK2/SRC inhibitor, curbs the growth of gastric cancer in vitro and in vivo by JAK2/SRC-STAT3 signaling pathways. Our results highlight that vortioxetine hydrobromide has the potential application in the chemoprevention of gastric cancer.