title: Increased phosphorylation of eIF2α in chronic myeloid leukemia cells stimulates secretion of matrix modifying enzymes.
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.
authors: Laboratory of Cytometry, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland.
authors: Paulina
authors: P
authors: Podszywalow-Bartnicka
authors: Laboratory of Lipid Biochemistry, Department of Biochemistry, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland.
authors: Anna
authors: A
authors: Cmoch
authors: Laboratory of Cytometry, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland.
authors: Magdalena
authors: M
authors: Wolczyk
authors: Laboratory of Cytometry, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland.
authors: Lukasz
authors: L
authors: Bugajski
authors: Laboratory of Mass Spectrometry, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
authors: Marta
authors: M
authors: Tkaczyk
authors: Laboratory of Mass Spectrometry, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
authors: Michal
authors: M
authors: Dadlez
authors: Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, USA.
authors: Margaret
authors: M
authors: Nieborowska-Skorska
authors: Lady Davis Institute for Medical Research, McGill University, Sir Mortimer B. Davis-Jewish General Hospital, Montreal, Quebec, Canada.|Department of Oncology, Faculty of Medicine, McGill University, Montreal, Quebec, Canada.
authors: Antonis E
authors: AE
authors: Koromilas
authors: Department of Microbiology and Immunology, Temple University School of Medicine, Philadelphia, USA.
authors: Tomasz
authors: T
authors: Skorski
authors: Laboratory of Cytometry, Nencki Institute of Experimental Biology of Polish Academy of Sciences, Warsaw, Poland.
authors: Katarzyna
authors: K
authors: Piwocka
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism; D001854:Bone Marrow Cells / Q000201:enzymology / Q000473:pathology; D002403:Cathepsins / Q000378:metabolism*; D002465:Cell Movement; D015852:Eukaryotic Initiation Factor-2 / Q000235:genetics / Q000378:metabolism*; D005109:Extracellular Matrix / Q000201:enzymology* / Q000473:pathology; D005347:Fibroblasts / Q000201:enzymology / Q000473:pathology; D006801:Humans; D020014:K562 Cells; D015464:Leukemia, Myelogenous, Chronic, BCR-ABL Positive / Q000201:enzymology* / Q000235:genetics / Q000473:pathology; D053505:Matrix Metalloproteinases, Secreted / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D019899:Paracrine Communication; D010766:Phosphorylation; D059748:Proteolysis; D015398:Signal Transduction; D017154:Stromal Cells / Q000201:enzymology / Q000473:pathology; D014162:Transfection; D059016:Tumor Microenvironment
chemical_list: C497109:ATF4 protein, human; D015852:Eukaryotic Initiation Factor-2; D051701:Activating Transcription Factor 4; D002403:Cathepsins; D053505:Matrix Metalloproteinases, Secreted
keywords: ATF4; CML; cell invasion; eIF2α; proteases