C21 steroid-enriched fraction refined from Marsdenia tenacissima inhibits hepatocellular carcinoma through the coordination of Hippo-Yap and PTEN-PI3K/AKT signaling pathways
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Yu Zhang1,3,*, Kaiqiang Li1,3,*, Youmin Ying2,*, Bingyu Chen1,*, Ke Hao1,3, Boxu Chen3, Yu Zheng3, Jianxin Lyu1, Xiangming Tong1,3, Xiaopan Chen3,4, Ying Wang1, Zhajun Zhan2, Wei Zhang1,3,** and Zhen Wang1,3,**
1Research Center of Blood Transfusion Medicine, Education Ministry Key Laboratory of Laboratory Medicine, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, China
2College of Pharmaceutical Science, Zhejiang University of Technology, Hangzhou 310014, China
3Key Laboratory of Tumor Molecular Diagnosis and Individualized Medicine of Zhejiang Province, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou 310014, China
4Department of Reproductive Endocrinology, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou 310014, China
*These authors have contributed equally to this work
**These authors are jointly supervised to this work
Zhen Wang, email: firstname.lastname@example.org
Wei Zhang, email: email@example.com
Keywords: hepatocellular carcinoma; Marsdenia tenacissima; Hippo-YAP signaling pathway; PI3K/AKT signaling pathway; C21 steroids
Received: September 04, 2017 Accepted: November 13, 2017 Published: November 30, 2017
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.
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