Oncotarget

Research Papers:

Caspase-3 and Caspase-6 cleave STAT1 in leukemic cells

Verena Licht, Katrin Noack, Bernhard Schlott, Martin Förster, Yvonne Schlenker, Andreas Licht, Oliver H. Krämer and Thorsten Heinzel _

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Oncotarget. 2014; 5:2305-2317. https://doi.org/10.18632/oncotarget.1911

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Abstract

Verena Licht1,2,*, Katrin Noack2,3,*, Bernhard Schlott1, Martin Förster4, Yvonne Schlenker4, Andreas Licht5, Oliver H. Krämer6, Thorsten Heinzel2

1 Leibniz Institute for Age Research – Fritz Lipmann Institute, Beutenbergstrasse 11, 07745 Jena, Germany

2 Friedrich-Schiller-Universität Jena, Centre for Molecular Biomedicine (CMB), Institute for Biochemistry and Biophysics, Hans-Knöll-Str. 2, 07745 Jena, Germany

3 Integrated Research and Treatment Center, Center for Sepsis Control and Care (CSCC), Jena University Hospital, , Erlanger Allee 101, 07747 Jena, Germany

4 Internal Medicine I, Pulmonary Medicine and Allergy/Immunology, University Clinics Jena, Erlanger Allee 101, 07747 Jena, Germany

5 Jena Bioscience GmbH, Loebstedter Strasse 80, 07749 Jena, Germany

6 Institut für Toxikologie, Universitätsmedizin Mainz, Obere Zahlbacher Str. 67, 55131 Mainz, Germany

* These authors corresponded equally to this work

Correspondence:

Oliver H. Krämer, email:

Thorsten Heinzel, email:

Keywords: Apoptosis, Caspase-3, Caspase-6, HDACi, Leukemia, STAT1

Received: February 18, 2014 Accepted: April 16, 2014 Published: April 18, 2014

Abstract

Signal Transducer and Activator of Transcription-1 (STAT1) is phosphorylated upon interferon (IFN) stimulation, which can restrict cell proliferation and survival. Nevertheless, in some cancers STAT1 can act in an anti-apoptotic manner. Moreover, certain malignancies are characterized by the overexpression and constitutive activation of STAT1. Here, we demonstrate that the treatment of transformed hematopoietic cells with epigenetic drugs belonging to the class of histone deacetylase inhibitors (HDACi) leads to the cleavage of STAT1 at multiple sites by caspase-3 and caspase-6. This process does not occur in solid tumor cells, normal hematopoietic cells, and leukemic cells that underwent granulocytic or monocytic differentiation. STAT1 cleavage was studied under cell free conditions with purified STAT1 and a set of candidate caspases as well as with mass spectrometry. These assays indicate that unmodified STAT1 is cleaved at multiple sites by caspase-3 and caspase-6. Our study shows that STAT1 is targeted by caspases in malignant undifferentiated hematopoietic cells. This observation may provide an explanation for the selective toxicity of HDACi against rapidly proliferating leukemic cells.


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