1. Increased phosphorylation of eIF2α in chronic myeloid leukemia cells stimulates secretion of matrix modifying enzymes
- Author
-
Katarzyna Piwocka, Magdalena Wolczyk, Marta Tkaczyk, Margaret Nieborowska-Skorska, Paulina Podszywalow-Bartnicka, Anna Cmoch, Tomasz Skorski, Antonis E. Koromilas, Michal Dadlez, and Lukasz Bugajski
- Subjects
0301 basic medicine ,Eukaryotic Initiation Factor-2 ,eIF2α ,Bone Marrow Cells ,Transfection ,Extracellular matrix ,03 medical and health sciences ,Cell Movement ,hemic and lymphatic diseases ,Leukemia, Myelogenous, Chronic, BCR-ABL Positive ,Matrix Metalloproteinases, Secreted ,Paracrine Communication ,medicine ,Extracellular ,Tumor Microenvironment ,Humans ,Neoplasm Invasiveness ,ATF4 ,Phosphorylation ,CML ,business.industry ,Myeloid leukemia ,Fibroblasts ,medicine.disease ,cell invasion ,Activating Transcription Factor 4 ,Cathepsins ,3. Good health ,Extracellular Matrix ,Leukemia ,030104 developmental biology ,medicine.anatomical_structure ,Oncology ,Immunology ,Cancer cell ,Proteolysis ,Unfolded protein response ,proteases ,Bone marrow ,Stromal Cells ,business ,K562 Cells ,Extracellular Matrix Degradation ,Signal Transduction ,Research Paper - Abstract
// Paulina Podszywalow-Bartnicka 1 , Anna Cmoch 2 , Magdalena Wolczyk 1 , Lukasz Bugajski 1 , Marta Tkaczyk 3 , Michal Dadlez 3 , Margaret Nieborowska-Skorska 4 , Antonis E. Koromilas 5, 6 , Tomasz Skorski 4 , Katarzyna Piwocka 1 1 Laboratory of Cytometry, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland 2 Laboratory of Lipid Biochemistry, Department of Biochemistry, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland 3 Laboratory of Mass Spectrometry, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland 4 Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, USA 5 Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada 6 Department of Oncology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada Correspondence to: Katarzyna Piwocka, email: k.piwocka@nencki.gov.pl Keywords: CML, eIF2α, ATF4, proteases, cell invasion Received: April 13, 2016 Accepted: October 17, 2016 Published: October 27, 2016 ABSTRACT 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.
- Published
- 2016