Microenvironment‐induced PIM kinases promote CXCR 4‐triggered mTOR pathway required for chronic lymphocytic leukaemia cell migration
| Autor: | Michal Galezowski, Karolina Piechna, Ewa Lech-Marańda, Ewa Jabłońska, Maja Wasylecka-Juszczyńska, Monika Noyszewska-Kania, Tomasz Sewastianik, Patryk Górniak, Przemyslaw Juszczynski, Anna Polak, Maciej Szydlowski, Emilia Bialopiotrowicz, Renata Windak, Bożena Katarzyna Budziszewska, Wojciech Czardybon, Bartosz Pula, Grazyna Nowak, Hanna Makuch-Łasica, Krzysztof Brzózka, Aleksandra Bluszcz, Krzysztof Warzocha, Katarzyna Borg |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Adult
Male 0301 basic medicine Receptors CXCR4 Stromal cell PIM1 Protein Serine-Threonine Kinases 03 medical and health sciences 0302 clinical medicine Proto-Oncogene Proteins c-pim-1 Cell Movement Proto-Oncogene Proteins hemic and lymphatic diseases Tumor Cells Cultured Tumor Microenvironment Humans Protein Kinase Inhibitors PIM kinase PI3K/AKT/mTOR pathway Aged Aged 80 and over CXCR4 Cell chemotaxis CD40 biology Gene Expression Regulation Leukemic Kinase Chemistry TOR Serine-Threonine Kinases Cell migration Original Articles Cell Biology Middle Aged Cell cycle Prognosis Leukemia Lymphocytic Chronic B-Cell 030104 developmental biology 030220 oncology & carcinogenesis mTOR biology.protein Cancer research Molecular Medicine Female Original Article chronic lymphocytic leukaemia |
| Zdroj: | Journal of Cellular and Molecular Medicine |
| ISSN: | 1582-4934 1582-1838 |
| DOI: | 10.1111/jcmm.13632 |
| Popis: | Lymph node microenvironment provides chronic lymphocytic leukaemia (CLL) cells with signals promoting their survival and granting resistance to chemotherapeutics. CLL cells overexpress PIM kinases, which regulate apoptosis, cell cycle and migration. We demonstrate that BCR crosslinking, CD40 stimulation, and coculture with stromal cells increases PIMs expression in CLL cells, indicating microenvironment‐dependent PIMs regulation. PIM1 and PIM2 expression at diagnosis was higher in patients with advanced disease (Binet C vs. Binet A/B) and in those, who progressed after first‐line treatment. In primary CLL cells, inhibition of PIM kinases with a pan‐PIM inhibitor, SEL24‐B489, decreased PIM‐specific substrate phosphorylation and induced dose‐dependent apoptosis in leukaemic, but not in normal B cells. Cytotoxicity of SEL24‐B489 was similar in TP53‐mutant and TP53 wild‐type cells. Finally, inhibition of PIM kinases decreased CXCR4‐mediated cell chemotaxis in two related mechanisms‐by decreasing CXCR4 phosphorylation and surface expression, and by limiting CXCR4‐triggered mTOR pathway activity. Importantly, PIM and mTOR inhibitors similarly impaired migration, indicating that CXCL12‐triggered mTOR is required for CLL cell chemotaxis. Given the microenvironment‐modulated PIM expression, their pro‐survival function and a role of PIMs in CXCR4‐induced migration, inhibition of these kinases might override microenvironmental protection and be an attractive therapeutic strategy in this disease. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|
Plný text