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Podszywalow-Bartnicka P , Cmoch A , Wolczyk M , Bugajski L , Tkaczyk M , Dadlez M , Nieborowska-Skorska M , Koromilas AE , Skorski T , Piwocka K
Increased phosphorylation of eIF2alpha in chronic myeloid leukemia cells stimulates secretion of matrix modifying enzymes
Oncotarget. 2016 Nov 29;7(48) :79706-79721
PMID: 27802179    PMCID: PMC5346746   
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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 alpha subunit (eIF2alpha), that phosphorylation of eIF2alpha (eIF2alpha-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 eIF2alpha-P/ATF4 pathway induces invasiveness of bone marrow stromal fibroblasts, suggesting that eIF2alpha-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.
Notes
1949-2553 Podszywalow-Bartnicka, Paulina Cmoch, Anna Wolczyk, Magdalena Bugajski, Lukasz Tkaczyk, Marta Dadlez, Michal Nieborowska-Skorska, Margaret Koromilas, Antonis E Skorski, Tomasz Piwocka, Katarzyna P30 CA006927/CA/NCI NIH HHS/United States R01 CA134458/CA/NCI NIH HHS/United States Journal Article United States Oncotarget. 2016 Nov 29;7(48):79706-79721. doi: 10.18632/oncotarget.12941.