Janus and PI3-kinases mediate glucocorticoid resistance in activated chronic leukemia cells
Autor: | Guizhei Wang, David Spaner, Stephanie Tung, Sina Oppermann, Jarkko Ylanko, David W. Andrews, Yonghong Shi, Brian Leber, Lindsay McCaw, Avery J. Lam |
---|---|
Rok vydání: | 2016 |
Předmět: |
0301 basic medicine
Chronic lymphocytic leukemia Buparlisib STAT3 Phosphatidylinositol 3-Kinases 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Tumor Cells Cultured medicine Humans Protein kinase B PI3K/AKT/mTOR pathway Janus Kinases glucocorticoids biology business.industry medicine.disease Leukemia Lymphocytic Chronic B-Cell cytokines 3. Good health Leukemia 030104 developmental biology Oncology chemistry Drug Resistance Neoplasm 030220 oncology & carcinogenesis Immunology Cancer research biology.protein chronic lymphocytic leukemia FOXO Idelalisib Janus kinase business hormones hormone substitutes and hormone antagonists Research Paper Signal Transduction |
Zdroj: | Oncotarget |
ISSN: | 1949-2553 |
Popis: | Glucorticoids (GCs) such as dexamethasone (DEX) remain important treatments for Chronic Lymphocytic Leukemia (CLL) but the mechanisms are poorly understood and resistance is inevitable. Proliferation centers (PC) in lymph nodes and bone marrow offer protection against many cytotoxic drugs and circulating CLL cells were found to acquire resistance to DEX-mediated killing in conditions encountered in PCs including stimulation by toll-like receptor agonists and interactions with stromal cells. The resistant state was associated with impaired glucocorticoid receptor-mediated gene expression, autocrine activation of STAT3 through Janus Kinases (JAKs), and increased glycolysis. The JAK1/2 inhibitor ruxolitinib blocked STAT3-phosphorylation and partially improved DEX-mediated killing of stimulated CLL cells in vitro but not in CLL patients in vivo. An automated microscopy-based screen of a kinase inhibitor library implicated an additional protective role for the PI3K/AKT/FOXO pathway. Blocking this pathway with the glycolysis inhibitor 2-deoxyglucose (2-DG) or the PI3K-inhibitors idelalisib and buparlisib increased DEX-mediated killing but did not block STAT3-phosphorylation. Combining idelalisib or buparlisib with ruxolitinib greatly increased killing by DEX. These observations suggest that glucocorticoid resistance in CLL cells may be overcome by combining JAK and PI3K inhibitors. |
Databáze: | OpenAIRE |
Externí odkaz: |