期刊
THERANOSTICS
卷 8, 期 17, 页码 4633-4648出版社
IVYSPRING INT PUBL
DOI: 10.7150/thno.26687
关键词
Amlexanox; prostate cancer; metastasis; IKK-epsilon/TBK1; mesenchymal-epithelial transition
资金
- Chinese Ministry of Science and Technology [2017YFA0102900]
- National Natural Science Foundation of China (NSFC) [81372189, 81630073]
- Science and Technology Commission of Shanghai Municipality [16JC1405700]
- Shanghai Eastern Hospital (Pudong) Stem Cell Research Base Fund
- KC Wong foundation
- NSFC [81772743]
- Shanghai Rising-Star Program [17QA1402100]
- Shanghai Youth Talent Support Program
- Shanghai Institutions of Higher Learning (The Program for Professor of Special Appointment (Young Eastern Scholar))
- School of Medicine, Shanghai Jiao Tong University (Excellent Youth Scholar Initiation Grant) [16XJ11003]
- Ren Ji Hospital [RJZZ14-010]
Tumor metastasis is the major cause of death for prostate cancer (PCa) patients. However, the treatment options for metastatic PCa are very limited. 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. We propose that small-molecule compounds that can reverse EMT or induce mesenchymal-epithelial transition (MET) of PCa cells may serve as drug candidates for anti-metastasis therapy. Methods: The promoters of CDH1 and VIM genes were sub-cloned to drive the expression of firefly and renilla luciferase reporter in a lentiviral vector. Mesenchymal-like PCa cells were infected with the luciferase reporter lentivirus and subjected to drug screening from a 1274 approved small-molecule drug library for the identification of agents to reverse EMT. The dosage-dependent effect of candidate compounds was confirmed by luciferase reporter assay and immunoblotting. Wound-healing assay, sphere formation, transwell migration assay, and in vivo intracardiac and orthotopic tumor xenograft experiments were used to evaluate the mobility, metastasis and tumor initiating capacity of PCa cells upon treatment. Possible downstream signaling pathways affected by the candidate compound treatment were analyzed by RNA sequencing and immunoblotting. Results: Drug screening identified Amlexanox, a drug used for recurrent aphthous ulcers, as a strong agent to reverse EMT. Amlexanox induced significant suppression of cell mobility, invasion, serial sphere formation and in vivo metastasis and tumor initiating capacity of PCa cells. Amlexanox treatment led to downregulation of the IKK-epsilon/TBK1/NF-kappa B signaling pathway. The effect of Amlexanox on EMT reversion and cell mobility inhibition can be mimicked by other IKK-epsilon/TBK1 inhibitors and rescued by reconstitution of dominant active NF-kappa B. Conclusions: Amlexanox can sufficiently suppress PCa metastasis by reversing EMT through downregulating the IKK-epsilon/TBK1/NF-kappa B signaling axis.
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