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      Matrine inhibits the proliferation and migration of lung cancer cells through regulation of the protein kinase B/glycogen synthase kinase-3β signaling pathways

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          Abstract

          Lung cancer is the leading cause of cancer-related mortality worldwide. Despite recent advances in treatment, lung cancer remains an incurable disease. Matrine, an active compound isolated from Sophora flavescens, has been demonstrated to inhibit proliferation and induce apoptosis of tumor cells. However, the protective effects and molecular mechanisms of matrine in lung cancer remain elusive. In the present study, the lung cancer cells H1299 and A549 were used to investigate how matrine affects the proliferation, migration and apoptosis of lung cancer cells in vitro. It was demonstrated that matrine is able to significantly suppress the proliferation and colony formation of lung cancer cells in vitro. Using cell apoptosis analysis, wound-healing and Transwell assays, it was demonstrated that matrine induced cellular apoptosis and inhibited the migration of lung cancer cells. Further experiments revealed that matrine significantly suppressed the phosphorylation of protein kinase B (Akt) and glycogen synthase kinase-3β (GSK-3β). The present results suggested that matrine inhibits lung cancer cell proliferation, and induces cell apoptosis by suppressing the Akt/GSK-3β signaling pathway, which demonstrated that matrine may have therapeutic potential for lung cancer.

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          L-type calcium channels regulate filopodia stability and cancer cell invasion downstream of integrin signalling

          Mounting in vitro, in vivo and clinical evidence suggest an important role for filopodia in driving cancer cell invasion. Using a high-throughput microscopic-based drug screen, we identify FDA-approved calcium channel blockers (CCBs) as potent inhibitors of filopodia formation in cancer cells. Unexpectedly, we discover that L-type calcium channels are functional and frequently expressed in cancer cells suggesting a previously unappreciated role for these channels during tumorigenesis. We further demonstrate that, at filopodia, L-type calcium channels are activated by integrin inside-out signalling, integrin activation and Src. Moreover, L-type calcium channels promote filopodia stability and maturation into talin-rich adhesions through the spatially restricted regulation of calcium entry and subsequent activation of the protease calpain-1. Altogether we uncover a novel and clinically relevant signalling pathway that regulates filopodia formation in cancer cells and propose that cycles of filopodia stabilization, followed by maturation into focal adhesions, directs cancer cell migration and invasion.
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            Nuclear Membrane-Targeted Gold Nanoparticles Inhibit Cancer Cell Migration and Invasion

            Most cancer patients die from metastasis. Recent studies have shown that gold nanoparticles (AuNPs) can slow down the migration/invasion speed of cancer cells and suppress metastasis. Since nuclear stiffness of the cell largely decreases cell migration, our hypothesis is that targeting AuNPs to the cell nucleus region could enhance nuclear stiffness, and therefore inhibit cell migration and invasion. Our results showed that upon nuclear targeting of AuNPs, the ovarian cancer cell motilities decrease significantly, compared with nontargeted AuNPs. Furthermore, using atomic force microscopy, we observed an enhanced cell nuclear stiffness. In order to understand the mechanism of cancer cell migration/invasion inhibition, the exact locations of the targeted AuNPs were clearly imaged using a high-resolution three-dimensional imaging microscope, which showed that the AuNPs were trapped at the nuclear membrane. In addition, we observed a greatly increased expression level of lamin A/C protein, which is located in the inner nuclear membrane and functions as a structural component of the nuclear lamina to enhance nuclear stiffness. We propose that the AuNPs that are trapped at the nuclear membrane both (1) add to the mechanical stiffness of the nucleus and (2) stimulate the overexpression of lamin A/C located around the nuclear membrane, thus increasing nuclear stiffness and slowing cancer cell migration and invasion.
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              TRPM 4 regulates Akt/ GSK 3‐β activity and enhances β‐catenin signaling and cell proliferation in prostate cancer cells

              Increased expression of the TRPM4 channel has been reported to be associated with the progression of prostate cancer. However, the molecular mechanism underlying its effect remains unknown. This work found that decreasing TRPM4 levels leads to the reduced proliferation of PC3 cells. This effect was associated with a decrease in total β‐catenin protein levels and its nuclear localization, and a significant reduction in Tcf/Lef transcriptional activity. Moreover, TRPM4 silencing increases the Ser33/Ser37/Thr41 β‐catenin phosphorylated population and reduces the phosphorylation of GSK‐3β at Ser9, suggesting an increase in β‐catenin degradation as the underlying mechanism. Conversely, TRPM4 overexpression in LNCaP cells increases the Ser9 inhibitory phosphorylation of GSK‐3β and the total levels of β‐catenin and its nonphosphorylated form. Finally, PC3 cells with reduced levels of TRPM4 showed a decrease in basal and stimulated phosphoactivation of Akt1, which is likely responsible for the decrease in GSK‐3β activity in these cells. Our results also suggest that the effect of TRPM4 on Akt1 is probably mediated by an alteration in the calcium/calmodulin‐EGFR axis, linking TRPM4 activity with the observed effects in β‐catenin‐related signaling pathways. These results suggest a role for TRPM4 channels in β‐catenin oncogene signaling and underlying mechanisms, highlighting this ion channel as a new potential target for future therapies in prostate cancer.
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                Author and article information

                Journal
                Exp Ther Med
                Exp Ther Med
                ETM
                Experimental and Therapeutic Medicine
                D.A. Spandidos
                1792-0981
                1792-1015
                August 2018
                07 June 2018
                07 June 2018
                : 16
                : 2
                : 723-729
                Affiliations
                Department of Respiratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120, P.R. China
                Author notes
                Correspondence to: Professor Zhongliang Guo, Department of Respiratory Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Road, Pudong New Area, Shanghai 200120, P.R. China, E-mail: drguozhl@ 123456163.com
                Article
                ETM-0-0-6266
                10.3892/etm.2018.6266
                6090456
                697e7653-8725-4d72-ae7b-aa47e3fa766e
                Copyright: © Xie 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
                : 14 October 2017
                : 02 February 2018
                Categories
                Articles

                Medicine
                lung cancer,matrine,proliferation,migration,invasion,apoptosis,protein kinase b,glycogen synthase kinase-3β

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