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

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 pro-mote 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.

Anti-tumoral activity of single and combined regorafenib treatments in preclinical models of liver and gastrointestinal cancers

“…Given its anti-tumor effects displayed in liver cancer, oleanolic acid coupled to regorafenib has been tested for advanced HCC. Both agents acted synergistically to inhibit the proliferation, EMT, migration and invasion of the PLC/PRF/5 cell line, which agrees with the suppression of tumor growth and lung metastasis in PLC-bearing mice 37 . In the same way, chlorogenic acid, a polyphenol present in the human diet, has shown positive effects in vitro in conjunction with regorafenib.…”

Modulation of Epithelial to Mesenchymal Transition Signaling Pathways by Olea Europaea and Its Active Compounds

“…Various studies observed these transitions to prove that the tested natural product was able to regulate EMT. For example, a recent study performed by Wang et al showed that oleanolic acid from olives inhibits the expression of mesenchymal-related protein (vimentin) while retaining the E-cadherin expression of hepatocellular carcinoma cell [57]. Other research on the action of Olea europaea and its active compounds on EMT pathway also reported the same pattern (Table 1); the affected pathway can be divided into two types: the SMAD-dependant and -independent pathways.…”

A Chinese Herbal Formula Suppresses Colorectal Cancer Migration and Vasculogenic Mimicry Through ROS/HIF-1α/MMP2 Pathway in Hypoxic Microenvironment

“…ex Miq. extraction) has antioxidant activity and attenuates tumor progression via inhibiting epithelial-mesenchymal transition (EMT) (Bai et al, 2018;Wang et al, 2018). Moreover, our previous study found that AAM could effectively prevent CRC progression via inhibiting tumor angiogenesis and vasculogenic mimicry (VM) in murine model (Manman Yu et al, 2011;Hou et al, 2016).…”