Abstract 5643A: Pleurotus pulmonarius extract suppresses liver cancer development and progression through VEGF-mediated autocrine regulation of PI3K/AKT pathway

Abstract

Abstract Hepatocellular Carcinoma (HCC) is one of the leading causes of cancer-related deaths. However, the conventional chemotherapies are not only limited by late diagnosis, locally advanced and metastasis, but also by various unexpected side effects. Because of the diverse pharmacological characteristics including non-toxicity, potent biological activity and solubility, natural phytochemicals are receiving more and more attention in the implication of chemoprevention and chemotherapy recently. Our previous studies have reported the anticancer effects of several mushroom polysaccharides including the Poria cocos and Pleurotus tuber-regium. Interestingly, an active polysaccharide and protein complex isolated from mushroom Pleurotus pulmonarius, coded as PP, was screened out based on the antioxidant activity study of the mushroom species collection in our lab. However, whether PP has anti-cancer effects in liver cancer cells and the underlying molecular mechanisms remain to be elucidated. This study aims to explore the anticancer effect of PP, and to investigate the signaling pathways responsible for its suppressing effect. Our results indicated that the exposure of liver cancer cells to PP not only reduced the cancer cell proliferation and invasion but also enhanced the drug-sensitivity to conventional chemotherapeutic drugs cisplatin. More importantly, both oral administration and intraperitoneal injection of PP significantly inhibited the tumor growth of liver cancer cells in nude mice. Furthermore, treatment of 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, suggesting the involvement of PI3K/AKT pathway in the function of PP in liver cancer cells. Interestingly, the data from western blot and ELISA (Enzyme-linked immunosorbent assay) demonstrated that treatment of liver cancer cells with PP reduced expression and secretion of vascular endothelial growth factor (VEGF), and addition of recombinant human VEGF attenuated the suppressive effects of PP on PI3K/AKT pathway and the cancer phenotypes. Taken together, our results indicated that PP, the active extract from Pleurotus pulmonarius, suppressed the proliferation, invasion, and drug-resistance of liver cancer cells in vitro and in vivo, and these effects are mediated by reduced expression and secretion of VEGF and the subsequent inhibited autocrine VEGF-induced activation of PI3K/AKT pathway. This study suggests potential therapeutic implication of PP in the treatment of liver cancer. The effects of PP on liver cancer stem cells and its chemopreventive effects in human liver cancer warrants further investigation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5643A. doi:1538-7445.AM2012-5643A