Int J Biol Sci 2022; 18(1):276-291. doi:10.7150/ijbs.66612 This issue

Research Paper

Verdinexor, a Selective Inhibitor of Nuclear Exportin 1, Inhibits the Proliferation and Migration of Esophageal Cancer via XPO1/c-Myc/FOSL1 Axis

Ling Ou1,6*, Xinyou Wang2*, Shumin Cheng1, Min Zhang1, Ruiqin Cui1, Chunxia Hu1, Shiyi Liu1, Qian Tang3,4, Yuying Peng3,4, Ruihuan Chai5, Shouxia Xie3, Shaoxiang Wang5✉, Wei Huang1✉, Xiao Wang3,4✉

1. Bacteriology & Antibacterial Resistance Surveillance Laboratory, Shenzhen Institute of Respiratory Diseases, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China.
2. The First District of Gastrointestinal Surgery, Sixth Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong, China.
3. Department of Pharmacy, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen 518020, Guangdong, China.
4. School of Pharmacy, Jinan University, Guangzhou 510630, Guangdong, China
5. School of Pharmaceutical Sciences, Shenzhen University Health Science Center, Shenzhen University, Shenzhen 518000, Guangdong, China.
6. School of Pharmaceutical Sciences (Shenzhen), Sun Yat-sen University, Shenzhen 518107, Guangdong, China.
* Co-first author

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Citation:
Ou L, Wang X, Cheng S, Zhang M, Cui R, Hu C, Liu S, Tang Q, Peng Y, Chai R, Xie S, Wang S, Huang W, Wang X. Verdinexor, a Selective Inhibitor of Nuclear Exportin 1, Inhibits the Proliferation and Migration of Esophageal Cancer via XPO1/c-Myc/FOSL1 Axis. Int J Biol Sci 2022; 18(1):276-291. doi:10.7150/ijbs.66612. Available from https://www.ijbs.com/v18p0276.htm

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Abstract

Graphic abstract

Esophageal carcinoma (EC) ranks sixth among cancers in mortality worldwide and effective drugs to reduce EC incidence and mortality are lacking. To explore potential anti-esophageal cancer drugs, we conducted drug screening and discovered that verdinexor, a selective inhibitor of nuclear exportin 1 (XPO1/CRM1), has anti-esophageal cancer effects both in vivo and in vitro. However, the mechanism and role of verdinexor in esophageal cancer remain unknown. In the present study, we observed that verdinexor inhibited the proliferation and migration of EC cells in vitro and suppressed tumor growth in vivo. Additionally, we found that verdinexor induced cleavage of PARP and downregulated XPO1, c-Myc, and FOSL1 expression. RNA-sequence analysis and protein-protein interaction (PPI) analysis revealed that verdinexor regulated the XPO1/c-Myc/FOSL1 axis. The results of immunoprecipitation and proximity ligation assays confirmed that verdinexor disrupted the interaction between XPO1 and c-Myc. Overexpression of c-Myc rescued the inhibition of cell proliferation and cell migration caused by verdinexor. Overexpressed FOSL1 restored the inhibited migration by verdinexor. Taken together, verdinexor inhibited cell proliferation and migration of esophageal cancer via XPO1/c-Myc/FOSL1 axis. Our findings provide a new option for the development of anti-esophageal cancer drugs.

Keywords: Verdinexor, XPO1, esophageal cancer, c-Myc, FOSL1