C21 steroid-enriched fraction refined from Marsdenia tenacissima inhibits hepatocellular carcinoma through the coordination of Hippo-Yap and PTEN-PI3K/AKT signaling pathways

Abstract

Marsdenia tenacissimae extraction (MTE), a traditional herbal medicine, has exhibited anti-tumor effects on a variety of cancers. However, its effectiveness and the mechanism of action in Hepatocellular carcinoma (HCC) has not been fully understood. In the present study, we demonstrate that C21 steroid-enriched fraction from MTE, which contains five main C21 steroids (FR5) exhibits obvious pharmacological activities on HCC cells in vitro and in vivo. FR5 induces apoptosis and inhibits proliferation and migration of HepG2 and Bel7402 cells in a dose and time dependent manner. Furthermore, in HCC cells, we found that FR5 inhibits Hippo pathway, leading to inactivation of YAP and increase of PTEN. Enhanced PTEN results in the inhibition of PI3K/AKT signaling pathway, inhibiting cell proliferation by FR5 and FR5-induced apoptosis. Moreover, it was proved that FR5 treatment could inhibit tumor growth in a HCC xenograft mouse model, and immunohistochemistry results showed FR5 treatment resulted in down-regulation of Bcl-2 and YAP, and up-regulation of PTEN and PI3K. Taken together, we found that FR5 effectively inhibits proliferation and induces apoptosis of HCC cells through coordinated inhibition of YAP in the Hippo pathway and AKT in the PI3K-PTEN-mTOR pathway, and suggest FR5 as a potential therapy for HCC.

C21 Fraction Refined from Marsdenia tenacissima-Induced Apoptosis is Enhanced by Suppression of Autophagy in Human Gastric Cell Lines

“… 23 , 24 Our previous research has shown that C21 fraction as an important component of MTE also has obvious cytotoxic effects in hepatic carcinoma cells by apoptosis through the PTEN/AKT/mTOR signaling pathway. 15 Our results also showed that C21 fraction greatly inhibits cell proliferation in gastric cancer cells ( Figure 1 ), and the reasons may be through cell cycle arrest and the obvious enhancement of apoptosis ( Figure 2 A,C). At the same time, cleaved PARP was observed in BGC-823 and AGS cell lines ( Figure 2 E).…”

“… 18 − 20 C21 fraction is separated from MTE and has been proven to inhibit proliferation and induce apoptosis of hepatoma carcinoma cells. 15 Recent research found that MTE, which is a water extract, could inhibit tumor activity by suppressing autophagy in lung cancer cells. 21 Whether this antitumor effect, which is caused by C21 fraction extracted from MTE, applies to gastric cancer had not been reported prior to this study.…”

“… 13 , 14 We found that C21 steroidal glycosides are widely found in MTE, and this study’s authors’ previous work has shown that treatment with C21 fraction from M. tenacissima could induce cell apoptosis through the PTEN-AKT-mTOR signal pathway. 15 However, the potential efficacy of C21 fraction on autophagy and whether autophagy inhibition can promote the anticancer effects of C21 has not yet been investigated.…”

<p>Melatonin Regulates Cisplatin Resistance and Glucose Metabolism Through Hippo Signaling in Hepatocellular Carcinoma Cells</p>

“…33 YAP is a crucial effector in Hippo signaling. Overexpression of YAP was detected in several cancers 46 and enabled to aid cell cycle progression via inducing cyclin proteins' expression and inhibiting p21. 47,48 In the present study, YAP silencing caused a reduced expression of Bcl-2 and GLUT-3, while its overexpression counteracted the MEL suppressive properties on HCC cells, indicating that MEL inhibited HCC growth partly through its inhibiting effect on YAP.…”

The Antitumor Activities of Marsdenia tenacissima

“…Acting as a potential tumor promoter, YAP overexpression has been connected with the progress of various tumors ( 45 ). Research has found that C21 steroids isolated from MTE can effectively induce apoptosis and inhibit the proliferation of HCC cells through inhibition of the PI3K/AKT/mTOR and YAP pathways together ( 28 ).…”