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

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.

Erinacine Facilitates the Opening of the Mitochondrial Permeability Transition Pore Through the Inhibition of the PI3K/ Akt/GSK-3β Signaling Pathway in Human Hepatocellular Carcinoma

“…This study provided evidence that erinacine facilitated the opening of MPTP and induced the apoptosis of HCC HepG2 cells in a dose-dependent manner, in In this study, we demonstrated that the PI3K/Akt-GSK-3β signaling pathway was activated in HCC tissues and cells, and that treatment with erinacine and LY294002 resulted in the inhibition of this pathway. A consistent study revealed that the extract of Pleurotus pulmonarius (an edible mushroom) inhibited the proliferation and invasion of HCC in vitro and in vivo through the suppression of the PI3K/Akt signaling pathway [29]. Moreover, the PI3K/ Akt/mTOR pathway was found to be activated in HCC and enhance invasion and metastasis through the up-regulation of the metalloproteinase-9 matrix in HCC [30].…”

The combination effects of Shen-Ling-Bai-Zhu on promoting apoptosis of transplanted H22 hepatocellular carcinoma in mice receiving chemotherapy

“…Akt in HCC can be usually activated by all kinds of tumor growth-promoting factors (such as PDGF and Angs), and result in increasing the generation of NF-КB, which can induce the expression of Bcl-2, Bcl-XL and Survivin to inhibit the activity of Caspase-3 and Caspase-7, and also promote the expression of XIAP to restrain the effects of Caspase-3/7/9 and finally antagonize the apoptosis-inducing effects of drugs (Hoesel et al, 2013;Kang et al, 2011;Lau et al, 2009;Xu et al, 2012). In this research, the potential interventions of SLBZP may exert through decreasing NF-КB, Bcl-2, Bcl-XL, Survivin and XIAP, and directly/indirectly increasing Caspase-3/9.…”

“…Tumor growth is enhanced by a variety of growth promoters including PDGF, VEGF and angiogenins (Romano, 2013;Hoesel et al, 2013;Kang et al, 2011;Linkous et al, 2012;Xu et al, 2012;Lau et al, 2009). They do so by activating Akt and NF-КB signaling pathways.…”

Targeting of growth factors in the treatment of hepatocellular carcinoma: The potentials of polysaccharides

“…Studies have suggested that, in HCC, PP reduces the expression of secretory VEGF, which in turn mediates autocrine regulation of PI3K/Akt signaling in xenograft BALB/c nude mice. PP can also enhance sensitivity to the chemotherapeutic drug cisplatin (68).…”