Increased phosphorylation of eIF2α in chronic myeloid leukemia cells stimulates secretion of matrix modifying enzymes
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Paulina Podszywalow-Bartnicka1, Anna Cmoch2, Magdalena Wolczyk1, Lukasz Bugajski1, Marta Tkaczyk3, Michal Dadlez3, Margaret Nieborowska-Skorska4, Antonis E. Koromilas5,6, Tomasz Skorski4, Katarzyna Piwocka1
1Laboratory of Cytometry, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
2Laboratory of Lipid Biochemistry, Department of Biochemistry, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland
3Laboratory of Mass Spectrometry, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
4Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, USA
5Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada
6Department of Oncology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada
Katarzyna Piwocka, email: email@example.com
Keywords: CML, eIF2α, ATF4, proteases, cell invasion
Received: April 13, 2016 Accepted: October 17, 2016 Published: October 27, 2016
Recent studies underscore the role of the microenvironment in therapy resistance of chronic myeloid leukemia (CML) cells and leukemia progression. We previously showed that sustained mild activation of endoplasmic reticulum (ER) stress in CML cells supports their survival and resistance to chemotherapy. We now demonstrate, using dominant negative non-phosphorylable mutant of eukaryotic initiation factor 2 α subunit (eIF2α), that phosphorylation of eIF2α (eIF2α-P), which is a hallmark of ER stress in CML cells, substantially enhances their invasive potential and modifies their ability to secrete extracellular components, including the matrix-modifying enzymes cathepsins and matrix metalloproteinases. These changes are dependent on the induction of activating transcription factor-4 (ATF4) and facilitate extracellular matrix degradation by CML cells. Conditioned media from CML cells with constitutive activation of the eIF2α-P/ATF4 pathway induces invasiveness of bone marrow stromal fibroblasts, suggesting that eIF2α-P may be important for extracellular matrix remodeling and thus leukemia cells-stroma interactions. Our data show that activation of stress response in CML cells may contribute to the disruption of bone marrow niche components by cancer cells and in this way support CML progression.
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