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Mol Cancer Ther. 2019 Jan;18(1):62-74. doi: 10.1158/1535-7163.MCT-18-0448. Epub 2018 Oct 8.

Oleanolic Acid Inhibits Epithelial-Mesenchymal Transition of Hepatocellular Carcinoma by Promoting iNOS Dimerization.

Wang H#1,2, Zhong W#1,2, Zhao J#3, Zhang H#1,2, Zhang Q1,2, Liang Y1, Chen S1, Liu H1, Zong S1, Tian Y1,2, Zhou H1,2, Sun T4,2, Liu Y4,5, Yang C4,2.

Author information

1
Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China.
2
State Key Laboratory of Medicinal Chemical Biology and College of Pharmacy, Nankai University, Tianjin, China.
3
Department of Pathology, Hospital of Shun Yi District, Beijing, China.
4
Tianjin Key Laboratory of Molecular Drug Research, Tianjin International Joint Academy of Biomedicine, Tianjin, China. cheng.yang@nankai.edu.cn liuyanrong1984@163.com sunrockmia@hotmail.com.
5
Drug Safety Evaluation Center, Tianjin International Joint Academy of Biomedicine, Tianjin, China.
#
Contributed equally

Abstract

Oleanolic acid exhibits extensive pharmacologic activities and takes significant antitumor effects. Its pharmacologic mechanism, however, still remained to be further clarified. In this study, we demonstrated that oleanolic acid attenuated the migration and invasion abilities, resulting in the suppression of the epithelial-mesenchymal transition (EMT) process in liver cancer cells, and inhibited the tumor growth of the peritoneal lymphocytes-bearing mice. We further proved that inducible nitric oxide synthase (iNOS) may be the potential target of oleanolic acid. We confirmed that oleanolic acid could promote the dimerization of iNOS, activating it, and subsequently increasing the production of nitric oxide. Further experiments indicated that oleanolic acid promoted the nitration of specific proteins and consequently suppressed their EMT-related biological functions. Furthermore, it has been confirmed that oleanolic acid enhanced the antitumor effects of regorafenib in liver cancer treatment. These results deepened our understanding of the pharmacologic mechanism of the antitumor effect oleanolic acid, and the importance of nitric oxide synthetase as a therapeutic target for liver cancer treatment.

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