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      Dicumarol inhibits PDK1 and targets multiple malignant behaviors of ovarian cancer cells

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          Abstract

          Pyruvate dehydrogenase kinase 1 (PDK1) is overexpressed in ovarian cancer and thus is a promising anticancer therapeutic target. Our previous work suggests that coumarin compounds are potential inhibitors of PDKs. In this study, we used the ovarian cancer cell line SKOV3 as the model system and examined whether dicumarol (DIC), a coumarin compound, could inhibit ovarian cancer through targeting PDK1. We showed that DIC potently inhibited the kinase activity of PDK1, shifted the glucose metabolism from aerobic glycolysis to oxidative phosphorylation, generated a higher level of reactive oxygen species (ROS), attenuated the mitochondrial membrane potential (MMP), induced apoptosis, and reduced cell viability in vitro. The same phenotypes induced by DIC also were translated in vivo, leading to significant suppression of xenograft growth. This study not only identifies a novel inhibitor for PDK1, but it also reveals novel anticancer mechanisms of DIC and provides a promising anticancer therapy that targets the Warburg effect.

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          PDK1-Dependent Metabolic Reprogramming Dictates Metastatic Potential in Breast Cancer.

          Fanny Dupuy, Sébastien Tabariès, Sylvia Andrzejewski … (2015)
          Metabolic reprogramming is a hallmark of cellular transformation, yet little is known about metabolic changes that accompany tumor metastasis. Here we show that primary breast cancer cells display extensive metabolic heterogeneity and engage distinct metabolic programs depending on their site of metastasis. Liver-metastatic breast cancer cells exhibit a unique metabolic program compared to bone- or lung-metastatic cells, characterized by increased conversion of glucose-derived pyruvate into lactate and a concomitant reduction in mitochondrial metabolism. Liver-metastatic cells displayed increased HIF-1α activity and expression of the HIF-1α target Pyruvate dehydrogenase kinase-1 (PDK1). Silencing HIF-1α reversed the glycolytic phenotype of liver-metastatic cells, while PDK1 was specifically required for metabolic adaptation to nutrient limitation and hypoxia. Finally, we demonstrate that PDK1 is required for efficient liver metastasis, and its expression is elevated in liver metastases from breast cancer patients. Our data implicate PDK1 as a key regulator of metabolism and metastatic potential in breast cancer.
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            Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1.

            Jung-whan Kim, Ping Gao, Yen-Chun Liu … (2007)
            Hypoxia is a pervasive microenvironmental factor that affects normal development as well as tumor progression. In most normal cells, hypoxia stabilizes hypoxia-inducible transcription factors (HIFs), particularly HIF-1, which activates genes involved in anaerobic metabolism and angiogenesis. As hypoxia signals a cellular deprivation state, HIF-1 has also been reported to counter the activity of MYC, which encodes a transcription factor that drives cell growth and proliferation. Since many human cancers express dysregulated MYC, we sought to determine whether HIF-1 would in fact collaborate with dysregulated MYC rather countering its function. Here, using the P493-6 Burkitt's lymphoma model with an inducible MYC, we demonstrate that HIF-1 cooperates with dysregulated c-Myc to promote glycolysis by induction of hexokinase 2, which catalyzes the first step of glycolysis, and pyruvate dehydrogenase kinase 1, which inactivates pyruvate dehydrogenase and diminishes mitochondrial respiration. We also found the collaborative induction of vascular endothelial growth factor (VEGF) by HIF-1 and dysregulated c-Myc. This study reports the previously unsuspected collaboration between HIF-1 and dysregulated MYC and thereby provides additional insights into the regulation of VEGF and the Warburg effect, which describes the propensity for cancer cells to convert glucose to lactate.
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              The pyruvate dehydrogenase complexes: structure-based function and regulation.

              Imran I. Patel, Natalia S. Nemeria, Frank Jordan … (2014)
              The pyruvate dehydrogenase complexes (PDCs) from all known living organisms comprise three principal catalytic components for their mission: E1 and E2 generate acetyl-coenzyme A, whereas the FAD/NAD(+)-dependent E3 performs redox recycling. Here we compare bacterial (Escherichia coli) and human PDCs, as they represent the two major classes of the superfamily of 2-oxo acid dehydrogenase complexes with different assembly of, and interactions among components. The human PDC is subject to inactivation at E1 by serine phosphorylation by four kinases, an inactivation reversed by the action of two phosphatases. Progress in our understanding of these complexes important in metabolism is reviewed. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.
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                Author and article information

                Contributors
                Aamir Ahmad: Role: Editor
                Journal
                Journal ID (nlm-ta): PLoS One
                Journal ID (iso-abbrev): PLoS ONE
                Journal ID (publisher-id): plos
                Journal ID (pmc): plosone
                Title: PLoS ONE
                Publisher: Public Library of Science (San Francisco, CA USA )
                ISSN (Electronic): 1932-6203
                Publication date (Electronic): 15 June 2017
                Publication date Collection: 2017
                Volume: 12
                Issue: 6
                Electronic Location Identifier: e0179672
                Affiliations
                [1 ]Department of Gynecological Oncology, The First Hospital of Jilin University, Changchun, China
                [2 ]College of Basic Medical Sciences, Jilin University, Changchun, China
                [3 ]State Key Laboratory of Microbial Metabolism, School of Life Sciences and Biotechnology, Shanghai Jiao Tong University, Shanghai, China
                University of South Alabama Mitchell Cancer Institute, UNITED STATES
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                • Conceptualization: YY XZ.

                • Data curation: WZ HX.

                • Formal analysis: JS LS.

                • Funding acquisition: LS XZ.

                • Investigation: WZ.

                • Methodology: JS YZ.

                • Project administration: YL LS.

                • Software: SY.

                • Supervision: YY XZ.

                • Validation: LS HX.

                • Visualization: WZ.

                • Writing – original draft: WZ.

                • Writing – review & editing: XZ JS.

                Author information
                http://orcid.org/0000-0001-7657-6020
                Article
                Publisher ID: PONE-D-17-12014
                DOI: 10.1371/journal.pone.0179672
                PMC ID: 5472302
                PubMed ID: 28617852
                SO-VID: 17ffe7d7-3927-4983-963c-f15e520caeeb
                Copyright © © 2017 Zhang et al
                License:

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Date received : 28 March 2017
                Date accepted : 1 June 2017
                Page count
                Figures: 6, Tables: 0, Pages: 18
                Funding
                Funded by: National Natural Science Foundation of China
                Award ID: 81472419
                Award Recipient :
                ORCID: http://orcid.org/0000-0001-7657-6020
                Funded by: National Natural Science Foundation of China
                Award ID: 81672948
                Award Recipient :
                ORCID: http://orcid.org/0000-0001-7657-6020
                Funded by: National Natural Science Foundation of China
                Award ID: 81272876
                Award Recipient :
                ORCID: http://orcid.org/0000-0001-7657-6020
                Funded by: National Natural Science Foundation of China
                Award ID: 31400681
                Award Recipient :
                ORCID: http://orcid.org/0000-0001-7657-6020
                This research was supported by the National Natural Science Foundation of China (No. 81472419, 81672948, 81272876, and 31400681).
                Categories
                Subject: Research Article
                Subject: Biology and Life Sciences
                Subject: Cell Biology
                Subject: Cell Processes
                Subject: Cell Death
                Subject: Apoptosis
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancers and Neoplasms
                Subject: Gynecological Tumors
                Subject: Ovarian Cancer
                Subject: Medicine and Health Sciences
                Subject: Oncology
                Subject: Cancer Treatment
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Metabolism
                Subject: Carbohydrate Metabolism
                Subject: Glucose Metabolism
                Subject: Research and Analysis Methods
                Subject: Immunologic Techniques
                Subject: Immunoassays
                Subject: Enzyme-Linked Immunoassays
                Subject: Biology and Life Sciences
                Subject: Biochemistry
                Subject: Enzymology
                Subject: Enzyme Inhibitors
                Subject: Kinase Inhibitors
                Subject: Physical Sciences
                Subject: Chemistry
                Subject: Chemical Compounds
                Subject: Coumarins
                Subject: Research and Analysis Methods
                Subject: Specimen Preparation and Treatment
                Subject: Staining
                Subject: Cell Staining
                Custom metadata
                Data Availability All relevant data are within the paper.

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