Journal
ONCOTARGET
Volume 8, Issue 66, Pages 110576-110591Publisher
IMPACT JOURNALS LLC
DOI: 10.18632/oncotarget.22833
Keywords
hepatocellular carcinoma; Marsdenia tenacissima; Hippo-YAP signaling pathway; PI3K/AKT signaling pathway; C21 steroids
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Funding
- National Natural Science Foundation of China [81501824, 81600595, 81772664]
- Natural Science Foundation of Zhejiang Province [Y15H280010, LY15C090004, Q16H070011, Y15C090021]
- Key project of Chinese medicine of Zhejiang Province [2015ZZ001]
- Traditional Chinese Medicine Outstanding Young Talent Foundation of Zhejiang Province [2014ZQ005]
- Medicine and Health Research Foundation of Zhejiang Province [2015ZDA002, 2015KYA028, 2016DTB001]
- Zhejiang Province People's Hospital [zry2015A005, zry2015B005]
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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 upregulation 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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