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      A covalent PIN1 inhibitor selectively targets cancer cells by a dual mechanism of action

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          Abstract

          The prolyl isomerase PIN1, a critical modifier of multiple signalling pathways, is overexpressed in the majority of cancers and its activity strongly contributes to tumour initiation and progression. Inactivation of PIN1 function conversely curbs tumour growth and cancer stem cell expansion, restores chemosensitivity and blocks metastatic spread, thus providing the rationale for a therapeutic strategy based on PIN1 inhibition. Notwithstanding, potent PIN1 inhibitors are still missing from the arsenal of anti-cancer drugs. By a mechanism-based screening, we have identified a novel covalent PIN1 inhibitor, KPT-6566, able to selectively inhibit PIN1 and target it for degradation. We demonstrate that KPT-6566 covalently binds to the catalytic site of PIN1. This interaction results in the release of a quinone-mimicking drug that generates reactive oxygen species and DNA damage, inducing cell death specifically in cancer cells. Accordingly, KPT-6566 treatment impairs PIN1-dependent cancer phenotypes in vitro and growth of lung metastasis in vivo.

          Abstract

          PIN1 is a promising therapeutic target for cancer treatment. In this study, the authors identify a covalent inhibitor of PIN1 with anti-tumour and anti-metastatic properties thanks to PIN1 inactivation and to the release, after binding to PIN1, of a quinone-mimicking compound that elicits reactive oxygen generation and causes DNA damage.

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          Most cited references37

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          NIH Image to ImageJ: 25 years of image analysis.

          For the past 25 years NIH Image and ImageJ software have been pioneers as open tools for the analysis of scientific images. We discuss the origins, challenges and solutions of these two programs, and how their history can serve to advise and inform other software projects.
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            Human breast cancer cell lines contain stem-like cells that self-renew, give rise to phenotypically diverse progeny and survive chemotherapy

            Introduction The phenotypic and functional differences between cells that initiate human breast tumors (cancer stem cells) and those that comprise the tumor bulk are difficult to study using only primary tumor tissue. We embarked on this study hypothesizing that breast cancer cell lines would contain analogous hierarchical differentiation programs to those found in primary breast tumors. Methods Eight human breast cell lines (human mammary epithelial cells, and MCF10A, MCF7, SUM149, SUM159, SUM1315 and MDA.MB.231 cells) were analyzed using flow cytometry for CD44, CD24, and epithelial-specific antigen (ESA) expression. Limiting dilution orthotopic injections were used to evaluate tumor initiation, while serial colony-forming unit, reconstitution and tumorsphere assays were performed to assess self-renewal and differentiation. Pulse-chase bromodeoxyuridine (5-bromo-2-deoxyuridine [BrdU]) labeling was used to examine cell cycle and label-retention of cancer stem cells. Cells were treated with paclitaxol and 5-fluorouracil to test selective resistance to chemotherapy, and gene expression profile after chemotherapy were examined. Results The percentage of CD44+/CD24- cells within cell lines does not correlate with tumorigenicity, but as few as 100 cells can form tumors when sorted for CD44+/CD24-/low/ESA+. Furthermore, CD44+/CD24-/ESA+ cells can self-renew, reconstitute the parental cell line, retain BrdU label, and preferentially survive chemotherapy. Conclusion These data validate the use of cancer cell lines as models for the development and testing of novel therapeutics aimed at eradicating cancer stem cells.
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              The prolyl isomerase PIN1: a pivotal new twist in phosphorylation signalling and disease.

              Protein phosphorylation regulates many cellular processes by causing changes in protein conformation. The prolyl isomerase PIN1 has been identified as a regulator of phosphorylation signalling that catalyses the conversion of specific phosphorylated motifs between the two completely distinct conformations in a subset of proteins. PIN1 regulates diverse cellular processes, including growth-signal responses, cell-cycle progression, cellular stress responses, neuronal function and immune responses. In line with the diverse physiological roles of PIN1, it has also been linked to several diseases that include cancer, Alzheimer's disease and asthma, and thus it might represent a novel therapeutic target.
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                Author and article information

                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group
                2041-1723
                09 June 2017
                2017
                : 8
                : 15772
                Affiliations
                [1 ]National Laboratory CIB (LNCIB), Area Science Park Padriciano , Trieste 34149, Italy
                [2 ]Department of Life Sciences, University of Trieste , Trieste 34127, Italy
                [3 ]Karyopharm Therapeutics , Newton, Massachusetts 02459, USA
                [4 ]Nerviano Medical Sciences Srl , Nerviano 20014, Italy
                [5 ]Department of Science and Drug Technology, University of Torino , Torino 10125, Italy
                [6 ]Elettra Sincrotrone Trieste S.C.p.A., Area Science Park Basovizza , Trieste 34149, Italy
                [7 ]Computational Biomedicine, Institute for Advanced Simulation (IAS-5) and Institute of Neuroscience and Medicine (INM-9), Forschungszentrum Jülich , Jülich 52425, Germany
                [8 ]Jülich Supercomputing Center (JSC), Forschungszentrum Jülich , Jülich 52425, Germany
                [9 ]Department of Oncology, Hematology and Stem Cell Transplantation, University Hospital Aachen, RWTH Aachen University , Aachen 52074, Germany
                [10 ]International Centre for Genetic Engineering and Biotechnology (ICGEB), Area Science Park Padriciano , Trieste 34149, Italy
                [11 ]IRCCS-Mario Negri Institute for Pharmacological Research , Milano 20156, Italy
                [12 ]Department of Surgery, Oncology and Gastroenterology, Oncology and Immunology Section, University of Padova , Padova 35128, Italy
                [13 ]Veneto Institute of Oncology (IOV)-IRCCS , Padova 35128, Italy
                Author notes
                [*]

                These authors contributed equally to this work.

                [†]

                Present address: Bioinformatics Core Facility, Center for Integrative Biology (CIBIO), University of Trento, Trento 38123, Italy

                [‡]

                Present address: Pi Therapeutics, P.O.B. 4044, Ness Ziona 7403635, Israel

                [§]

                Present address: Evogene Ltd., P.O.B. 2100, Rehovot 7612002, Israel

                Author information
                http://orcid.org/0000-0002-7156-5434
                http://orcid.org/0000-0002-2590-3332
                http://orcid.org/0000-0001-6733-795X
                Article
                ncomms15772
                10.1038/ncomms15772
                5472749
                28598431
                c062f0de-9c84-4f0c-a4c7-a52ccf3f6765
                Copyright © 2017, The Author(s)

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/

                History
                : 25 August 2016
                : 27 April 2017
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