Urolithin A Inhibits Epithelial–Mesenchymal Transition in Lung Cancer Cells via P53-Mdm2-Snail Pathway

Abstract

Feng Cheng,1,* Jintao Dou,1,2,* Yong Zhang,1,3,* Xiang Wang,1,4,* Huijun Wei,5 Zhijian Zhang,1,5 Yuxiang Cao,4,6 Zhihao Wu1,5,7,8 1Research Laboratory of Tumor Microenvironment, Wannan Medical College, Wuhu, 241001, People’s Republic of China; 2School of Anesthesiology, Wannan Medical College, Wuhu, 241001, People’s Republic of China; 3School of Clinical Medicine, Wannan Medical College, Wuhu, 241001, People’s Republic of China; 4School of Laboratory Medicine, Wannan Medical College, Wuhu, 241001, People’s Republic of China; 5School of Preclinical Medicine, Wannan Medical College, Wuhu, 241001, People’s Republic of China; 6Provincial Engineering Laboratory for Screening and Re-Evaluation of Active Compounds of Herbal Medicines in Southern Anhui, Wannan Medical College, Wuhu, 241001, People’s Republic of China; 7Anhui Province Key Laboratory of Active Biological Macro-Molecules Research, Wannan Medical College, Wuhu, 241001, People’s Republic of China; 8Key Laboratory of Non-Coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, 241001, People’s Republic of China*These authors contributed equally to this workCorrespondence: Zhihao WuResearch Laboratory of Tumor Microenvironment, Wannan Medical College, Wuhu, 241001, People’s Republic of ChinaEmail [email protected]: The epithelial-to-mesenchymal transition (EMT) is a fundamental process in tumor progression that endows cancer cells with migratory and invasive potential. Snail, a zinc finger transcriptional repressor, plays an important role in the induction of EMT by directly repressing the key epithelial marker E-cadherin. Here, we assessed the effect of urolithin A, a major metabolite from pomegranate ellagitannins, on Snail expression and EMT process.Methods: The role of Snail in urolithin A-induced EMT inhibition in lung cancer cells was explored by wound healing assay and cell invasion assay. The qRT-PCR and CHX assay were performed to investigate how urolithin A regulates Snail expression. Immunoprecipitation assays were established to determine the effects of urolithin A in mdm2-Snail interaction. In addition, the expression of p53 was manipulated to explore its effect on the expression of mdm2 and Snail.Results: The urolithin A dose-dependently upregulated epithelial marker and decreased mesenchymal markers in lung cancer cells. In addition, exposure to urolithin A decreased cell migratory and invasive capacity. We have further demonstrated that urolithin A inhibits lung cancer cell EMT by decreasing Snail protein expression and activity. Mechanistically, urolithin A disrupts the interaction of p53 and mdm2 which leads Snail ubiquitination and degradation.Conclusion: We conclude that urolithin A could inhibit EMT process by controlling mainly Snail expression. These results highlighted the role of pomegranate in regulation of EMT program in lung cancer.Keywords: urolithin A, ellagitannin metabolite, epithelial–mesenchymal transition, Snail, mdm2, lung cancer

Keywords

• urolithin a
• ellagitannin metabolite
• epithelial-mesenchymal transition
• snail
• mdm2
• lung cancer