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      Fangchinoline suppresses growth and metastasis of melanoma cells by inhibiting the phosphorylation of FAK

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          Abstract

          Melanoma is a malignant tumor with high degree of malignancy, metastasis and high mortality. The etiology of melanoma has not been fully elucidated, and there is no effective drug for the complete treatment of melanoma. In recent years, many traditional Chinese herbal medicines have played an important role in clinical treatment and experimental research on cancer. As a natural product, fangchinoline has the characteristics of enhancing immune function, low toxicity and good liver protection features, so it is considered to be a new type of anticancer drug. In the present study, we found that fangchinoline has inhibitory effects on the proliferation and metastasis of A375 and A875 cells in a concentration-dependent manner. Fangchinoline inhibited the proliferation of A375 and A875 cell activity with IC 50 values of 12.41 and 16.20 µM. We also found that fangchinoline could significantly reduce the phosphorylation of Focal adhesion kinase (FAK). In summary, we demonstrated that fangchinoline inhibits the proliferation and metastasis of melanoma cells by suppressing FAK and its downstream signaling pathway. More importantly, we provide a novel mechanism that fangchinoline could be an effective candidate for the treatment of melanoma.

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          Most cited references25

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          Targeting FAK in human cancer: from finding to first clinical trials.

          It is twenty years since Focal Adhesion Kinase (FAK) was found to be overexpressed in many types of human cancer. FAK plays an important role in adhesion, spreading, motility, invasion, metastasis, survival, angiogenesis, and recently has been found to play an important role as well in epithelial to mesenchymal transition (EMT), cancer stem cells and tumor microenvironment. FAK has kinase-dependent and kinase independent scaffolding, cytoplasmic and nuclear functions. Several years ago FAK was proposed as a potential therapeutic target; the first clinical trials were just reported, and they supported further studies of FAK as a promising therapeutic target. This review discusses the main functions of FAK in cancer, and specifically focuses on recent novel findings on the role of FAK in cancer stem cells, microenvironment, epithelial-to-mesenchymal transition, invasion, metastasis, and also highlight new approaches of targeting FAK and critically discuss challenges that lie ahead for its targeted therapeutics. The review provides a summary of translational approaches of FAK-targeted and combination therapies and outline perspectives and future directions of FAK research.
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            Fangchinoline induces autophagic cell death via p53/sestrin2/AMPK signalling in human hepatocellular carcinoma cells.

            Fangchinoline is a novel anti-tumour agent with little known of its cellular and molecular mechanisms of action. Here we have investigated the mode of cell death induced by fangchinoline and its underlying mechanism in two human hepatocellular carcinoma cell lines, HepG2 and PLC/PRF/5. Apoptosis and autophagy were monitored in fangchinoline-treated HepG2 and PLC/PRF/5 cells by histological methods. The signal transduction pathways involved in activation of autophagy were examined, using immunoblotting, real-time PCR and siRNA techniques. Fangchinoline did not induce apoptosis in HepG2 and PLC/PRF/5 cells but triggered, dose-dependently, autophagy, an alternative mode of cell death which may contribute to fangchinoline's anti-tumour action. Nuclear translocation of p53 was involved in induction of autophagy by fangchinoline, followed by selective transactivation of the autophagy-related gene sestrin2 and initiation of the autophagic process. Signalling by the AMP-activated protein kinase was also involved as a downstream target of sestrin2 and induced mTOR-independent autophagic cell death in both cell lines. siRNA for Atg 5 or pharmacological block of p53 abolished fangchinoline-induced autophagy and inhibition of autophagy switched cell death to apoptosis in these cells, suggesting that cell death is irreversible once autophagy is induced by fangchinoline. Fangchinoline is a highly specific agent inducing autophagic cell death in hepatocellular carcinoma cells with a novel mechanism, which elucidates the potential of fangchinoline to potentiate programmed cell death in cancer cells. © 2011 The Authors. British Journal of Pharmacology © 2011 The British Pharmacological Society.
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              Melanoma chondroitin sulfate proteoglycan enhances FAK and ERK activation by distinct mechanisms

              Melanoma chondroitin sulfate proteoglycan (MCSP) is an early cell surface melanoma progression marker implicated in stimulating tumor cell proliferation, migration, and invasion. Focal adhesion kinase (FAK) plays a pivotal role in integrating growth factor and adhesion-related signaling pathways, facilitating cell spreading and migration. Extracellular signal–regulated kinase (ERK) 1 and 2, implicated in tumor growth and survival, has also been linked to clinical melanoma progression. We have cloned the MCSP core protein and expressed it in the MCSP-negative melanoma cell line WM1552C. Expression of MCSP enhances integrin-mediated cell spreading, FAK phosphorylation, and activation of ERK1/2. MCSP transfectants exhibit extensive MCSP-rich microspikes on adherent cells, where it also colocalizes with α4 integrin. Enhanced activation of FAK and ERK1/2 by MCSP appears to involve independent mechanisms because inhibition of FAK activation had no effect on ERK1/2 phosphorylation. These results indicate that MCSP may facilitate primary melanoma progression by enhancing the activation of key signaling pathways important for tumor invasion and growth.
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                Author and article information

                Journal
                Oncol Rep
                Oncol. Rep
                Oncology Reports
                D.A. Spandidos
                1021-335X
                1791-2431
                January 2017
                30 May 2017
                30 May 2017
                : 38
                : 1
                : 63-70
                Affiliations
                Department of Reconstructive and Plastic Surgery, The General Hospital of Shenyang Military Region, Shenyang, Liaoning 110840, P.R. China
                Author notes
                Correspondence to: Dr Kai Tao or Dr Peng Chang, Department of Reconstructive and Plastic Surgery, The General Hospital of Shenyang Military Region, No. 83 Wenhua Road, Shenhe, Shenyang, Liaoning 110840, P.R. China, E-mail: luzongzhengxing@ 123456sina.com , E-mail: cp17625@ 123456163.com
                [*]

                Contributed equally

                Article
                or-38-01-0063
                10.3892/or.2017.5678
                5492563
                28560386
                96ac30b1-e19a-4a33-823a-595824ca8fad
                Copyright: © Shi et al.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.

                History
                : 12 December 2016
                : 22 May 2017
                Categories
                Articles

                fangchinoline,melanoma,focal adhesion kinase,signaling pathway

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