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Acute Myeloid Leukemia
Inhibition of protein disulfide isomerase induces differentiation of acute myeloid leukemia cells
Ferrata Storti Foundation
Justyna Chlebowska-Tuz,1,2,3 Olga Sokolowska,1,2,4 Pawel Gaj,1,5
Michal Lazniewski,6,7 Malgorzata Firczuk,1 Karolina Borowiec,1
Hanna Sas-Nowosielska,8 Malgorzata Bajor,1 Agata Malinowska,9 Angelika Muchowicz,1 Kavita Ramji,1 Piotr Stawinski,10 Mateusz Sobczak,2 Zofia Pilch,1 Anna Rodziewicz-Lurzynska,11 Malgorzata Zajac,12
Krzysztof Giannopoulos,12 Przemyslaw Juszczynski,13 Grzegorz W. Basak,14 Dariusz Plewczynski,6,15 Rafal Ploski,10 Jakub Golab1,16 and Dominika Nowis1,2,17
Haematologica 2018 Volume 103(11):1843-1852
1Department of Immunology, Medical University of Warsaw; 2Laboratory of Experimental Medicine, Center of New Technologies, University of Warsaw; 3Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw; 4Postgraduate School of Molecular Medicine, Medical University of Warsaw; 5Laboratory of Human Cancer Genetics, Center of New Technologies, University of Warsaw; 6Laboratory of Functional and Structural Genomics, Center of New Technologies, University of Warsaw; 7Department of Physical Chemistry, Faculty of Pharmacy, Medical University of Warsaw; 8Laboratory of Imaging Tissue Structure and Function, Nencki Institute of Experimental Biology, Polish Academy of Sciences, Warsaw; 9Laboratory of Mass Spectrometry, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw; 10Department of Medical Genetics, Center of Biostructure Research, Medical University of Warsaw; 11Department of Laboratory Diagnostics, Faculty of Health Sciences, Medical University of Warsaw; 12Department of Experimental Hematooncology, Medical University of Lublin; 13Department of Experimental Hematology, Institute of Hematology and Transfusion Medicine, Warsaw; 14Department of Hematology, Oncology and Internal Diseases, Medical University of Warsaw; 15Faculty of Mathematics and Information Science, Warsaw University of Technology, Warsaw; 16Center for Preclinical Research and Technology, Medical University of Warsaw and 17Genomic Medicine, Medical University of Warsaw, Poland
ABSTRACT
Acute myeloid leukemia is a malignant disease of immature myeloid cells. Despite significant therapeutic effects of differ- entiation-inducing agents in some acute myeloid leukemia sub- types, the disease remains incurable in a large fraction of patients. Here we show that SK053, a thioredoxin inhibitor, induces differenti- ation and cell death of acute myeloid leukemia cells. Considering that thioredoxin knock-down with short hairpin RNA failed to exert antiproliferative effects in one of the acute myeloid leukemia cell lines, we used a biotin affinity probe-labeling approach to identify potential molecular targets for the effects of SK053. Mass spectrome- try of proteins precipitated from acute myeloid leukemia cells incubat- ed with biotinylated SK053 used as a bait revealed protein disulfide isomerase as a potential binding partner for the compound. Biochemical, enzymatic and functional assays using fluorescence life- time imaging confirmed that SK053 binds to and inhibits the activity of protein disulfide isomerase. Protein disulfide isomerase knock- down with short hairpin RNA was associated with inhibition of cell growth, increased CCAAT enhancer-binding protein a levels, and induction of differentiation of HL-60 cells. Molecular dynamics simu- lation followed by the covalent docking indicated that SK053 binds to the fourth thioredoxin-like domain of protein disulfide isomerase. Differentiation of myeloid precursor cells requires the activity of CCAAT enhancer-binding protein a, the function of which is impaired in acute myeloid leukemia cells through various mecha- nisms, including translational block by protein disulfide isomerase.
Correspondence:
d.nowis@cent.uw.edu.pl or jakub.golab@wum.edu.pl
Received: February 3, 2018. Accepted: July 10, 2018. Pre-published: July 12, 2018.
doi:10.3324/haematol.2018.190231
Check the online version for the most updated information on this article, online supplements, and information on authorship & disclosures: www.haematologica.org/content/103/11/1843
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