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      OncoTargets and Therapy (submit here)

      This international, peer-reviewed Open Access journal by Dove Medical Press focuses on the pathological basis of cancers, potential targets for therapy and treatment protocols to improve the management of cancer patients. Publishing high-quality, original research on molecular aspects of cancer, including the molecular diagnosis, since 2008. Sign up for email alerts here. 50,877 Monthly downloads/views I 4.345 Impact Factor I 7.0 CiteScore I 0.81 Source Normalized Impact per Paper (SNIP) I 0.811 Scimago Journal & Country Rank (SJR)

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      Cryptanshinone Inhibits the Glycolysis and Inhibits Cell Migration Through PKM2/β-Catenin Axis in Breast Cancer

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          Abstract

          Background

          Breast cancer is one of the most prevalent gynecologic malignancies worldwide. Despite the high sensitivity in response to chemotherapy, drug resistance occurred frequently in clinical treatment. Cryptotanshinone (CTS) is a herbal medicine and has been identified as an anti-inflammatory and anti-oxidative drug.

          Methods

          In vitro assays, including the cell proliferation assay, colony formation assay, Western blot analysis, transwell migration/invasion assays, and cell scratch assay were used to explore the biological activities and working mechanism of CTS. Breast cancer cells were also transfected with PKM2 expressing vectors to define the molecular mechanisms involved in CTS-mediated anti-tumor activity.

          Results

          We found that CTS shows anti-proliferative effects and decreases the clonogenic ability of breast cancer cells. We also found that CTS inhibited the migration and invasion activity of MCF-7 and MDA-MB-231 cells by different analyzed methods. CTS also downregulated the levels of glycolysis-related proteins, such as PKM2, LDHA, and HK2. In addition, overexpression of PKM2 recovered CTS-mediated suppression of cell proliferation, colony formation, and cell mobility of breast cancer cells. We also found PKM2 was significantly overexpressed in tumor tissues and invasive ductal breast carcinoma compared to normal tissues and patients with high PKM2 expression had worse overall survival and metastasis-free survival outcomes.

          Conclusion

          CTS inhibited the proliferation, migration, and invasion of breast cancer cells. The involved mechanism may refer to the downregulation of the PKM2/β-catenin axis.

          Most cited references38

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          Pyruvate kinase M2 activators promote tetramer formation and suppress tumorigenesis

          Cancer cells engage in a metabolic program to enhance biosynthesis and support cell proliferation. The regulatory properties of pyruvate kinase M2 (PKM2) influence altered glucose metabolism in cancer. PKM2 interaction with phosphotyrosine-containing proteins inhibits enzyme activity and increases availability of glycolytic metabolites to support cell proliferation. This suggests that high pyruvate kinase activity may suppress tumor growth. We show that expression of PKM1, the pyruvate kinase isoform with high constitutive activity, or exposure to published small molecule PKM2 activators inhibit growth of xenograft tumors. Structural studies reveal that small molecule activators bind PKM2 at the subunit interaction interface, a site distinct from that of the endogenous activator fructose-1,6-bisphosphate (FBP). However, unlike FBP, binding of activators to PKM2 promotes a constitutively active enzyme state that is resistant to inhibition by tyrosine-phosphorylated proteins. These data support the notion that small molecule activation of PKM2 can interfere with anabolic metabolism.
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            Breast cancer as a systemic disease: a view of metastasis.

            Breast cancer is now the most frequently diagnosed cancer and leading cause of cancer death in women worldwide. Strategies targeting the primary tumour have markedly improved, but systemic treatments to prevent metastasis are less effective; metastatic disease remains the underlying cause of death in the majority of patients with breast cancer who succumb to their disease. The long latency period between initial treatment and eventual recurrence in some patients suggests that a tumour may both alter and respond to the host systemic environment to facilitate and sustain disease progression. Results from studies in animal models suggest that specific subtypes of breast cancer may direct metastasis through recruitment and activation of haematopoietic cells. In this review, we focus on data implicating breast cancer as a systemic disease. © 2013 The Association for the Publication of the Journal of Internal Medicine.
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              Pyruvate kinase type M2: a key regulator of the metabolic budget system in tumor cells.

              Cell proliferation only proceeds when metabolism is capable of providing a budget of metabolic intermediates that is adequate to ensure both energy regeneration and the synthesis of cell building blocks in sufficient amounts. In tumor cells, the glycolytic pyruvate kinase isoenzyme M2 (PKM2, M2-PK) determines whether glucose is converted to lactate for regeneration of energy (active tetrameric form, Warburg effect) or used for the synthesis of cell building blocks (nearly inactive dimeric form). This review discusses the regulation mechanisms of pyruvate kinase M2 expression by different transcription factors as well as the regulation of pyruvate kinase M2 activity by direct interaction with certain oncoproteins, tyrosine and serine phosphorylation, binding of phosphotyrosine peptides, association with other glycolytic and non glycolytic enzymes, the promyelocytic leukemia tumor suppressor protein, as well as metabolic intermediates. An intervention in the regulation mechanisms of the expression, activity and tetramer to dimer ratio of pyruvate kinase M2 has severe consequences for metabolism as well as proliferation and tumorigenic capacity of the cells which makes this enzyme a promising target for potential therapeutic approaches. The quantification of the dimeric form of pyruvate kinase M2 (Tumor M2-PK) in plasma and stool allows early detection of tumors and therapy control. Several different mechanisms may induce a translocation of pyruvate kinase M2 into the nucleus. The role of pyruvate kinase M2 in the nucleus is complex as witnessed by evidence of its effect both as pro-proliferative as well as pro-apoptotic stimuli. Copyright © 2010 Elsevier Ltd. All rights reserved.
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                Author and article information

                Journal
                Onco Targets Ther
                Onco Targets Ther
                ott
                ott
                OncoTargets and therapy
                Dove
                1178-6930
                25 August 2020
                2020
                : 13
                : 8629-8639
                Affiliations
                [1 ]Graduate Institute of Biomedical Informatics, College of Medical Science and Technology, Taipei Medical University , Taipei City, Taiwan
                [2 ]Ningbo AJcore Biosciences Inc, High-tech Zone , Ningbo City, People’s Republic of China
                [3 ]Division of General Surgery, Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University , Taipei City, Taiwan
                [4 ]Division of General Surgery, Department of Surgery, Shuang Ho Hospital, Taipei Medical University , New Taipei City, Taiwan
                [5 ]Ningbo AllBiolife Biotech Inc, High-tech Zone , Ningbo City, People’s Republic of China
                [6 ]Department of Emergency Medicine, Shuang Ho Hospital, Taipei Medical University, Institute of Injury Prevention and Control, Taipei Medical University , Taipei City, Taiwan
                [7 ]Information Technology Office, Shuang Ho Hospital, Taipei Medical University , New Taipei City, Taiwan
                Author notes
                Correspondence: Yu-Ting Yeh Information Technology Office, Shuang Ho Hospital, Taipei Medical University , New Taipei City, TaiwanTel +886 22490088 Ext 8901 Email yuting@tmu.edu.tw
                [*]

                These authors contributed equally to this work

                Author information
                http://orcid.org/0000-0002-1035-4238
                http://orcid.org/0000-0001-5112-1556
                http://orcid.org/0000-0002-6861-3319
                Article
                239134
                10.2147/OTT.S239134
                7457727
                d7a94d0f-ca1f-4916-a26f-700ef7b95692
                © 2020 Zhou et al.

                This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms.php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License ( http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms ( https://www.dovepress.com/terms.php).

                History
                : 19 November 2019
                : 03 August 2020
                Page count
                Figures: 6, References: 47, Pages: 11
                Funding
                Funded by: Ministry of Science and Technology grants from Taiwan;
                Award ID: (104-2320-B-038-053-MY3)
                Award ID: (108-2745-8-038-002-)
                Award ID: (108-2320-B-038-020-) and (108-2314-B-038-121-)
                This work was supported by the Ministry of Science and Technology grants from Taiwan (104-2320-B-038-053-MY3), (108-2745-8-038-002-), (108-2320-B-038-020-), (108-2314-B-038-121-) and (109-2314-B-038-121-).
                Categories
                Original Research

                Oncology & Radiotherapy
                cryptotanshinone,glycolysis,breast cancer,pkm2,migration
                Oncology & Radiotherapy
                cryptotanshinone, glycolysis, breast cancer, pkm2, migration

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