Extract of <em>Pleurotus pulmonarius</em> Suppresses Liver Cancer Development and Progression through Inhibition of VEGF-Induced PI3K/AKT Signaling Pathway

<div><p>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 <em>Pleurotus</em> 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 <em>Pleurotus pulmonarius</em> (PP) in liver cancer cells. Our results indicated that exposure of liver cancer cells to PP not only significantly reduced the <em>in vitro</em> 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 <em>in vitro</em> and <em>in vivo</em>, 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 <em>in vitro</em> and <em>in vivo</em>, 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.</p>