Blockage of epithelial to mesenchymal transition and upregulation of let 7b are critically involved in ursolic acid induced apoptosis in malignant mesothelioma cell

Autor: Sung-Hoon Kim, Hee Jeong Kim, Gunho Won, Eun Jung Sohn, Ilho Lee, Ji Hyun Lee, Sang Wook Yoon
Rok vydání: 2016
Předmět:
Mesothelioma
0301 basic medicine
Epithelial-Mesenchymal Transition
Lung Neoplasms
Blotting
Western
Cell
Population
Caspase 3
Vimentin
Real-Time Polymerase Chain Reaction
Transfection
Applied Microbiology and Biotechnology
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Ursolic acid
Cell Line
Tumor
medicine
Humans
Epithelial–mesenchymal transition
education
Molecular Biology
let 7b
Ecology
Evolution
Behavior and Systematics
miRNA array
education.field_of_study
biology
Cell growth
Chemistry
Cell Cycle
Mesothelioma
Malignant
apoptosis
Cell Biology
epithelial and mesenchymal transition
Triterpenes
MicroRNAs
030104 developmental biology
medicine.anatomical_structure
Apoptosis
030220 oncology & carcinogenesis
Immunology
Cancer research
biology.protein
Research Paper
Developmental Biology
Zdroj: International Journal of Biological Sciences
ISSN: 1449-2288
DOI: 10.7150/ijbs.13453
Popis: 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.
Databáze: OpenAIRE
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