Abstract
Liver cancer or hepatocellular carcinoma is one of the leading causes of cancer-related deaths. Conventional chemotherapies are limited by the development of drug resistance and various side effects. Because of its non-toxicity and potent biopharmacological activity, metabolites derived from mushrooms have received more attention in cancer therapy. Our previous studies have demonstrated the anticancer effects of polysaccharide-protein complexes derived from the Pleurotus mushrooms. The aim of this study was to investigate the underlying molecular mechanism of the anticancer activity of a hot water extract containing a polysaccharide-protein complex isolated from Pleurotus pulmonarius (PP) in liver cancer cells. Our results indicated that exposure of liver cancer cells to PP not only significantly reduced the in vitro cancer cell proliferation and invasion but also enhanced the drug-sensitivity to the chemotherapeutic drug Cisplatin. Both oral administration and intraperitoneal injection of PP significantly inhibited the tumor growth in xenograft BALB/c nude mice. PP triggered a marked suppression of the PI3K/AKT signaling pathway in liver cancer cells in vitro and in vivo, and overexpression of the constitutively active form of AKT, Myr-AKT, abrogated this effect and the inhibited proliferation and invasion by PP. Both western blot and ELISA results showed that PP-treated liver cancer cells had reduced expression and secretion of vascular endothelial growth factor (VEGF). Addition of recombinant human VEGF attenuated the inhibitory effects of PP on PI3K/AKT pathway and the cancer phenotypes. Our results demonstrated that PP suppressed the proliferation, invasion, and drug-resistance of liver cancer cells in vitro and in vivo, mediated by the inhibition of autocrine VEGF-induced PI3K/AKT signaling pathway. This study suggests the potential therapeutic implication of PP in the treatment of human liver cancer.
Highlights
Liver cancer is the fifth most prevalent cancer and the third leading cause of all cancer-related deaths in the world [1,2,3]
Western blot indicated a dose-dependent reduction in the expression of cyclin B1, an important G2 checkpoint protein, in the two liver cancer cells, suggesting that Pleurotus pulmonarius (PP)-induced G2 phase cell cycle arrest might be mediated by the down-regulated expression of cyclin B1 (Fig. 1C)
To exclude the possibility that the anticancer effect of polysaccharide-protein complex isolated from Pleurotus pulmonarius are non-specific, polysaccharide-protein complex isolated from another Pleurotus mushroom, Pleurotus tuber-regium (PTR) was applied as control, suggesting the specific effect of PP (Fig. S1)
Summary
Liver cancer is the fifth most prevalent cancer and the third leading cause of all cancer-related deaths in the world [1,2,3]. Natural phytochemicals and metabolites from plants are receiving increasing attention for their pharmacological effects in treatment and prevention of cancer because of their low toxicity and potential biological activity [9]. Both in vitro and in vivo studies have shown that these bioactive natural products can inhibit the initiation, promotion, and progression of carcinogenesis by interfering the signaling pathways in human cancer cells and their consumption has become a promising chemopreventive and chemotherapeutic strategy against cancers [10,11]. Crude extract of the polysaccharides present in Ganoderma lucidum was found to have anti-metastatic effects through the modulation of the PI3K/ AKT pathway [20]
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