title: Blockage of epithelial to mesenchymal transition and upregulation of let 7b are critically involved in ursolic acid induced apoptosis in malignant mesothelioma cell.
abstract: Malignant pleural mesothelioma (MPN), which is caused by asbestos exposure, is one of aggressive lung tumors. In the present study, we elucidated the anti-tumor mechanism of ursolic acid in malignant mesotheliomas. Ursolic acid significantly exerted cytotoxicity in a time and dose dependent manner in H28, H2452 and MSTO-211H mesothelioma cells and inhibited cell proliferation by colony formation assay in a dose-dependent fashion. Also, ursolic acid treatment accumulated the sub-G1 population, attenuated the expression of procapase 9, cyclin D1, pAKT, p-glycogen synthase kinase 3-alpha/beta (pGSK3α/β), β-catenin and nuclear factor kappa-light-chain-enhancer of activated B cells (NFkB) and also cleaved caspase 3 and poly (ADP-ribose) polymerase (PARP) in mesothelioma cells. Furthermore, ursolic acid treatment blocked epithelial and mesenchymal transition (EMT) molecules by activating E-cadherin as an epithelial marker and attenuating Vimentin, and Twist as mesenchymal molecules. Interestingly, miRNA array revealed that 23 miRNAs (>2 folds) including let-7b and miRNA3613-5p, miRNA134 and miRNA196b were significantly upregulated while 33 miRNAs were downregulated in ursolic acid treated H2452 cells. Furthermore, overexpression of let 7b using let-7b mimics enhanced the antitumor effect of ursolic acid to attenuate the expression of procaspases 3, pro-PARP, pAKT, β-catenin and Twist and increase sub-G1 accumulation in H2452 mesothelioma cells. Overall, our findings suggest that ursolic acid induces apoptosis via inhibition of EMT and activation of let7b in mesothelioma cells as a potent chemotherapeutic agent for treatment of malignant mesotheliomas.
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea.
authors.forename: Eun Jung
authors.initials: EJ
authors.lastname: Sohn
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea.
authors.forename: Gunho
authors.initials: G
authors.lastname: Won
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea.
authors.forename: Jihyun
authors.initials: J
authors.lastname: Lee
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea.
authors.forename: Sang Wook
authors.initials: SW
authors.lastname: Yoon
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea.
authors.forename: Ilho
authors.initials: I
authors.lastname: Lee
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea.
authors.forename: Hee Jeong
authors.initials: HJ
authors.lastname: Kim
authors.affiliation: College of Korean Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea.
authors.forename: Sung-Hoon
authors.initials: SH
authors.lastname: Kim
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D006801:Humans; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology*; D008654:Mesothelioma / Q000378:metabolism* / Q000473:pathology*; D000086002:Mesothelioma, Malignant; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D014162:Transfection; D014315:Triterpenes / Q000494:pharmacology*; D000097245:Ursolic Acid
chemical_list: D035683:MicroRNAs; D014315:Triterpenes; D000097245:Ursolic Acid
keywords: Ursolic acid; apoptosis; epithelial and mesenchymal transition; let 7b; mesothelioma; miRNA array