Inhibiting Epithelial-to-mesenchymal Transition And Prostate Cancer Metastasis By Repositioning The Aphthous Ulcer Drug Amlexanox

Prostate cancer(PCa)is one of most common cancers and highest causes of cancer-related mortality in men worldwide.Tumor metastasis,which remains to be incurable,is the major contributor to PCa related death.Therefor treatment approaches to target prostate tumor metastasis is in urgent need.Epithelial-mesenchymal transition(EMT)has been reported to be an indispensable step for tumor metastasis and is suggested to associate with acquisition of cancer stem cell(CSC)attributes.Thus we consider EMT as a potential screening target in discovering new anti-metastasis treatment.Herein we establish an EMT reporter system based on a firefly or renilla luciferase reporter driven by promoters of CDH1 and VIM genes,respectively.High-throughput drug screening from an approved drug library identifies Amlexanox,a commonly used drug to treat aphthous ulcers,to be a strong EMT inhibitor.Amlexanox induced significant suppression on cell mobility,invasion,serial sphere formation and in vivo metastasis and tumor initiating capacity of PCa cells.Amlexanox treatment led to downregulation of the IKKε/ TBK1/ NF-κB signaling pathway.The inhibitory effect of Amlexanox on EMT and cell mobility can be mimicked by other IKKε/TBK1 inhibitors and rescued by reconstitution of dominant active NF-κB.In summary,Amlexanox is identified as a potent epithelial-mesenchymal transition inhibitor via a high-throughput screening system and significantly suppresses PCa cell migration,metastasis and tumor initiation capacity in vitro and in vivo.Considering the known safety as well as the pharmacokinetic and pharmacodynamic profile of Amlexanox,our findings suggest a great potential of repositioning Amlexanox as a new anti-metastatic drug for PCa.