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International Journal Of Bilogical Sciences

.: Home > International Journal Of Bilogical Sciences > 2016 > Volume 12 Number 11 > Eun Jung Sohn*, Gunho Won*, Jihyun Lee, Sang Wook Yoon, Hee Jeong Kim, Sung-Hoon Kim

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

Eun Jung Sohn*, Gunho Won*, Jihyun Lee, Sang Wook Yoon, Hee Jeong Kim, Sung-Hoon Kim
College of Korean Medicine, Kyung Hee University, Seoul, 130-701, Republic of Korea * Equally contributed  Corresponding author: Sung-Hoon Kim, K.M.D., Ph.D., Cancer Preventive Material Development Research Center, College of Oriental Medicine, Kyung Hee University, 1 Hoegi-dong, Dongdaemun-gu, Seoul 130-701, South Korea. Tel: 82-2-961-9233; Fax: 82-2-964-1064; E-mail: sungkim7@khu.ac.kr
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.

Keywords :
Ursolic acid; mesothelioma; apoptosis; epithelial and mesenchymal transition; miRNA array; let 7b

Date Deposited : 07 Nov 2016 20:48

Last Modified : 07 Nov 2016 20:48

Official URL: http://www.ijbs.com/v12i11

Volume 12, Number 11, October 2016

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