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      Role of Wnt/β-catenin pathway in inducing autophagy and apoptosis in multiple myeloma cells

      research-article
      , ,
      Oncology Letters
      D.A. Spandidos
      multiple myeloma, Wnt/β-catenin signaling, autophagy, apoptosis

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          Abstract

          β-catenin is the downstream effector of the Wnt signaling pathway, which regulates cell proliferation and differentiation. Activation of the Wnt/β-catenin signaling pathway has been shown to positively correlate with prognosis in several types of malignancies. The present study aimed to determine the role of β-catenin in multiple myeloma (MM) cells using lentiviruses expressing small interfering RNA (siRNA). The expression of β-catenin in the MM cell line RPMI-8826 was evaluated following β-catenin knockdown by the siRNA. Subsequently, the activation of autophagy in MM cells was assessed by transmission electron microscopy and western blot analyses. Cell apoptosis and the expression of apoptosis-related proteins following β-catenin silencing was investigated by flow cytometry and western blotting, respectively. A significant decrease in β-catenin expression was observed in the MM cell line expressing β-catenin-specific siRNA. Activation of autophagy was induced by β-catenin silencing, as evidenced by increases in the number of autophagic vacuoles and the expression of the autophagy-related proteins microtubule-associated protein 1 light chain 3 and Beclin-1. Furthermore, the expression of 5′-adenosine monophosphate-activated protein kinase was increased, and that of mechanistic target of rapamycin was decreased, following β-catenin silencing. In addition, there was an increase in the rate of apoptosis of MM cells following β-catenin silencing, accompanied by increased protein expression of phosphorylated p53, active caspase-3 and B-cell lymphoma (Bcl)-2-associated X protein, and decreased protein expression of Bcl-2. The results of the present study suggested that β-catenin silencing induced autophagy and apoptosis in MM cells. To the best of our knowledge, this is the first study to demonstrate that a β-catenin deficiency induces autophagy in MM cells. These findings suggested that inhibition of β-catenin could be a potential therapeutic target for patients with MM.

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          Most cited references20

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          Identification of c-MYC as a target of the APC pathway.

          The adenomatous polyposis coli gene (APC) is a tumor suppressor gene that is inactivated in most colorectal cancers. Mutations of APC cause aberrant accumulation of beta-catenin, which then binds T cell factor-4 (Tcf-4), causing increased transcriptional activation of unknown genes. Here, the c-MYC oncogene is identified as a target gene in this signaling pathway. Expression of c-MYC was shown to be repressed by wild-type APC and activated by beta-catenin, and these effects were mediated through Tcf-4 binding sites in the c-MYC promoter. These results provide a molecular framework for understanding the previously enigmatic overexpression of c-MYC in colorectal cancers.
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            Understanding multiple myeloma pathogenesis in the bone marrow to identify new therapeutic targets.

            Multiple myeloma is a plasma cell malignancy characterized by complex heterogeneous cytogenetic abnormalities. The bone marrow microenvironment promotes multiple myeloma cell growth and resistance to conventional therapies. Although multiple myeloma remains incurable, novel targeted agents, used alone or in combination, have shown great promise to overcome conventional drug resistance and improve patient outcome. Recent oncogenomic studies have further advanced our understanding of the molecular pathogenesis of multiple myeloma, providing the framework for new prognostic classification and identifying new therapeutic targets.
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              beta-catenin signaling and cancer.

              P J Morin (1999)
              Since its discovery as a protein associated with the cytoplasmic region of E-cadherin, beta-catenin has been shown to perform two apparently unrelated functions: it has a crucial role in cell-cell adhesion in addition to a signaling role as a component of the Wnt/wg pathway. Wnt/wg signaling results in beta-catenin accumulation and transcriptional activation of specific target genes during development. It is now apparent that deregulation of beta-catenin signaling is an important event in the genesis of a number of malignancies, such as colon cancer, melanoma, hepatocellular carcinoma, ovarian cancer, endometrial cancer, medulloblastoma pilomatricomas, and prostate cancer. beta-catenin mutations appear to be a crucial step in the progression of a subset of these cancers, suggesting an important role in the control of cellular proliferation or cell death. The APC/beta-catenin pathway is highly regulated and includes players such as GSK3-beta, CBP, Groucho, Axin, Conductin, and TCF. c-MYC and cyclin D1 were recently identified as a key transcriptional targets of this pathway and additional targets are likely to emerge. Published 1999 John Wiley & Sons, Inc.
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                Author and article information

                Journal
                Oncol Lett
                Oncol Lett
                OL
                Oncology Letters
                D.A. Spandidos
                1792-1074
                1792-1082
                December 2016
                18 October 2016
                18 October 2016
                : 12
                : 6
                : 4623-4629
                Affiliations
                Department of Hematology, First Affiliation Hospital of China Medical University, Shenyang, Liaoning 110001, P.R. China
                Author notes
                Correspondence to: Dr Yan Li, Department of Hematology, First Affiliation Hospital of China Medical University, 155 Nanjing Road, Shenyang, Liaoning 110001, P.R. China, E-mail: beeperchild@ 123456163.com
                Article
                OL-0-0-5289
                10.3892/ol.2016.5289
                5228543
                28105169
                cd5024a8-53cf-486d-aab6-e87f4a2bdaa7
                Copyright: © Su 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
                : 27 May 2015
                : 05 October 2016
                Categories
                Articles

                Oncology & Radiotherapy
                multiple myeloma,wnt/β-catenin signaling,autophagy,apoptosis
                Oncology & Radiotherapy
                multiple myeloma, wnt/β-catenin signaling, autophagy, apoptosis

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