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      CIP2A is a target of bortezomib in human triple negative breast cancer cells

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          Abstract

          Introduction

          Triple negative breast cancer (TNBC) is very aggressive and currently has no specific therapeutic targets, such as hormone receptors or human epidermal growth factor receptor type 2 (HER2); therefore, prognosis is poor. Bortezomib, a proteasome inhibitor, may exert efficacy in TNBC through its multiple cellular effects. Here, we tested the efficacy of bortezomib and examined the drug mechanism in breast cancer cells.

          Methods

          Five breast cancer cell lines: TNBC HCC-1937, MDA-MB-231, and MDA-MB-468; HER2-overexpressing MDA-MB-453; and estrogen receptor positive MCF-7 were used for in vitro studies. Apoptosis was examined by both flow cytometry and Western Blot. Signal transduction pathways in cells were assessed by Western Blot. Gene silencing was done by small interfering RNA (siRNA). In vivo efficacy of bortezomib was tested in nude mice with breast cancer xenografts. Immunohistochemical study was performed on tumor tissues from patients with TNBC.

          Results

          Bortezomib induced significant apoptosis, which was independent of its proteasome inhibition, in the three TNBC cell lines, but not in MDA-MB-453 or MCF-7 cells. Furthermore, cancerous inhibitor of protein phosphatase 2A (CIP2A), a cellular inhibitor of protein phosphatase 2A (PP2A), mediated the apoptotic effect of bortezomib. We showed that bortezomib inhibited CIP2A in association with p-Akt downregulation in a dose- and time-dependent manner in all sensitive TNBC cells, whereas no alterations in CIP2A expression and p-Akt were noted in bortezomib-resistant cells. Overexpression of CIP2A upregulated p-Akt and protected MDA-MB-231 and MDA-MB-468 cells from bortezomib-induced apoptosis, whereas silencing CIP2A by siRNA overcame the resistance to bortezomib-induced apoptosis in MCF-7 cells. In addition, bortezomib downregulated CIP2A mRNA but did not affect the degradation of CIP2A protein. Furthermore, bortezomib exerted in vivo antitumor activity in HCC-1937 xenografted tumors, but not in MCF-7 tumors. Bortezomib downregulated CIP2A expression in the HCC-1937 tumors but not in the MCF-7 tumors. Importantly, CIP2A expression is readily detectable in tumor samples from TNBC patients.

          Conclusions

          CIP2A is a major determinant mediating bortezomib-induced apoptosis in TNBC cells. CIP2A may thus be a potential therapeutic target in TNBC.

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          Most cited references41

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          Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival.

          Mitogen-activated protein kinase (MAPK) pathways constitute a large modular network that regulates a variety of physiological processes, such as cell growth, differentiation, and apoptotic cell death. The function of the ERK pathway has been depicted as survival-promoting, in essence by opposing the proapoptotic activity of the stress-activated c-Jun NH(2)-terminal kinase (JNK)/p38 MAPK pathways. However, recently published work suggests that extracellular regulated kinase (ERK) pathway activity is suppressed by JNK/p38 kinases during apoptosis induction. In this review, we will summarize the current knowledge about JNK/p38-mediated mechanisms that negatively regulate the ERK pathway. In particular, we will focus on phosphatases (PP2A, MKPs) as inhibitors of ERK pathway activity in regulating apoptosis. A model proposed in this review places the negative regulation of the ERK pathway in a central position for the cellular decision-making process that determines whether cells will live or die in response to apoptosis-promoting signals. In addition, we will discuss the potential functional relevance of negative regulation of ERK pathway activity, for physiological and pathological conditions (e.g., cellular transformation).
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            Proteasome inhibitors in cancer therapy: lessons from the first decade.

            The ubiquitin-proteasome pathway is involved in intracellular protein turnover, and its function is crucial to cellular homeostasis. First synthesized as probes of proteolytic processes, proteasome inhibitors began to be thought of as potential drug candidates when they were found to induce programmed cell death preferentially in transformed cells. They made their first leap into the clinic to be tested as therapeutic agents 10 years ago, and since then, great strides have been made in defining their mechanisms of action, their clinical efficacy and toxicity, and some of their limitations in the form of resistance pathways. Validation of the ubiquitin-proteasome pathway as a target for cancer therapy has come in the form of approvals of the first such inhibitor, bortezomib, for relapsed/refractory multiple myeloma and mantle cell lymphoma, for which this agent has become a standard of care. Lessons learned from this first-in-class agent are now being applied to the development of a new generation of proteasome inhibitors that hold the promise of efficacy in bortezomib-resistant disease and possibly in a broader spectrum of diseases. This saga provides a salient example of the promise of translational medicine and a paradigm by which other agents may be successfully brought from the bench to the bedside.
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              The tumor suppressor PP2A is functionally inactivated in blast crisis CML through the inhibitory activity of the BCR/ABL-regulated SET protein.

              The oncogenic BCR/ABL kinase activity induces and maintains chronic myelogenous leukemia (CML). We show here that, in BCR/ABL-transformed cells and CML blast crisis (CML-BC) progenitors, the phosphatase activity of the tumor suppressor PP2A is inhibited by the BCR/ABL-induced expression of the PP2A inhibitor SET. In imatinib-sensitive and -resistant (T315I included) BCR/ABL+ cell lines and CML-BC progenitors, molecular and/or pharmacological activation of PP2A promotes dephosphorylation of key regulators of cell proliferation and survival, suppresses BCR/ABL activity, and induces BCR/ABL degradation. Furthermore, PP2A activation results in growth suppression, enhanced apoptosis, restored differentiation, impaired clonogenic potential, and decreased in vivo leukemogenesis of imatinib-sensitive and -resistant BCR/ABL+ cells. Thus, functional inactivation of PP2A is essential for BCR/ABL leukemogenesis and, perhaps, required for blastic transformation.
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                Author and article information

                Journal
                Breast Cancer Res
                Breast Cancer Res
                Breast Cancer Research : BCR
                BioMed Central
                1465-5411
                1465-542X
                2012
                26 April 2012
                : 14
                : 2
                : R68
                Affiliations
                [1 ]Department of Surgery, Taipei Veterans General Hospital, No. 201 Sec. 2 Shih-Pai Road, Taipei 112, Taiwan
                [2 ]Institute of Biopharmaceutical Sciences, National Yang-Ming University, No. 155 Sec. 2 Li-Nong Street, Taipei 112, Taiwan
                [3 ]School of Medicine, National Yang-Ming University, No. 155 Sec. 2 Li-Nong Street, Taipei 112, Taiwan
                [4 ]Division of Hematology and Oncology, Department of Medicine, Taipei Veterans General Hospital, No. 201 Sec. 2 Shih-Pai Road, Taipei 112, Taiwan
                [5 ]Department of Pathology, St. Martin De Porres Hospital, No. 565 Sec. 2 Daya Road, Chiayi 600, Taiwan
                [6 ]Department of Medical Research, National Taiwan University Hospital, No. 7 Chung-Shan S Road, Taipei 100, Taipei, Taiwan
                [7 ]National Center of Excellence for Clinical Trial and Research, National Taiwan University Hospital, No. 7 Chung-Shan S Road, Taipei 100, Taiwan
                Article
                bcr3175
                10.1186/bcr3175
                3446403
                22537901
                b7af9cc1-4a92-457c-8a73-c6705b5c1c5f
                Copyright ©2012 Tseng et al.; licensee BioMed Central Ltd.

                This is an open access article distributed under the terms of the Creative Commons Attribution License ( http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 12 August 2011
                : 16 April 2012
                : 26 April 2012
                Categories
                Research Article

                Oncology & Radiotherapy
                Oncology & Radiotherapy

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