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.
Highlights
Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and the third leading cause of cancerrelated mortality worldwide [1]
Five compounds 1~5 were isolated from FR5 by preparative high performance liquid chromatography (HPLC) (Figure 1A) and identified by nuclear magnetic resonance (NMR) analyses and comparison with the literatures to be: tenacissoside G [18], tenacissoside I [18], marsdenoside A [19], marsdenoside B [19], and marsdenoside C [19] (Figure 1B, Table 1)
Looking further upstream in the PI3K/AKT pathway, it was observed that FR5induced upregulation of PTEN was abolished in the YAP-knockdown cells (Figure 7B, 7E).Altogether, these results indicate the effect of FR5 on PI3K/AKT pathway was modulated by Hippo-YAP pathway through the mediation of tumor suppressor PTEN
Summary
Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer and the third leading cause of cancerrelated mortality worldwide [1]. Marsdenia tenacissima extraction (MTE, called Xiao-Ai-Ping injection) is a traditional herbal medicine with significant anti-tumor effect, as adjuvant therapy after chemotherapy and radiation therapy [5], for esophageal cancer, lung cancer, leukemia and hepatocellular carcinoma [6,7,8,9]. More than forty C21 steroidal glycosides have been isolated from MTE [10], and studies demonstrate that components of C21 steroids are specific cytotoxic to various cancer cells [11] through various mechanisms, such as inhibition of tumor growth, induction of apoptosis and cell cycle arrest, and reverse of multidrug resistance [12,13]. FR5 was purified from MTE by HPLC to make more efficient and less toxic effect
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