Reconstitution of PTEN activity by CK2 inhibitors and interference with the PI3-K/Akt cascade counteract the antiapoptotic effect of human stromal cells in chronic lymphocytic leukemia
Autor: | Christoph C. Zielinski, Josef D. Schwarzmeier, Andrea Hoelbl, Ulrich Jaeger, Elena Ponath, Susanne Schnabl, Medhat Shehata, Alexander Gaiger, Sigrun Badrnya, Claudia Lehner, Rainer Hubmann, Markus Duechler, Dita Demirtas, Martin Hilgarth |
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Rok vydání: | 2010 |
Předmět: |
Stromal cell
Chronic lymphocytic leukemia Immunology Apoptosis Bone Marrow Cells Biochemistry medicine Humans PTEN Tensin Casein Kinase II Protein kinase B Cells Cultured PI3K/AKT/mTOR pathway Tumor microenvironment biology PTEN Phosphohydrolase Cell Biology Hematology medicine.disease Leukemia Lymphocytic Chronic B-Cell Leukemia biology.protein Cancer research Phosphatidylinositol 3-Kinase Stromal Cells Proto-Oncogene Proteins c-akt |
Zdroj: | Blood. 116:2513-2521 |
ISSN: | 1528-0020 0006-4971 |
Popis: | Evidence suggests that tumor microenvironment is critically involved in supporting survival of chronic lymphocytic leukemia (CLL) cells. However, the molecular mechanisms of this effect and the clinical significance are not fully understood. We applied a microenvironment model to explore the interaction between CLL cells and stromal cells and to elucidate the role of phosphatidylinositol 3 kinase (PI3-K)/Akt/phosphatase and tensin homolog detected on chromosome 10 (PTEN) cascade in this process and its in vivo relevance. Primary human stromal cells from bone marrow, lymph nodes, and spleen significantly inhibited spontaneous apoptosis of CLL cells. Pan–PI3-K inhibitors (LY294002, wortmannin, PI-103), isotype-specific inhibitors of p110α, p110β, p110γ, and small interfering RNA against PI3-K and Akt1 counteracted the antiapoptotic effect of the stromal cells. Induction of apoptosis was associated with a decrease in phosphatidylinositol-3,4,5-triphosphate, PI3-K–p85, and dephosphorylation of phosphatidylinositol-dependent kinase-1 (PDK-1), Akt1, and PTEN. Freshly isolated peripheral blood mononuclear cells from patients with CLL (n = 44) showed significantly higher levels of phosphorylated Akt1, PDK-1, PTEN, and CK2 than healthy persons (n = 8). CK2 inhibitors (4,5,6,7-tetrabromo-1H-benzotriazole, apigenin, and 5,6-dichloro-1-β-D-ribofuranosylbenzimidazol) decreased phosphorylation of PTEN and Akt, induced apoptosis in CLL cells, and enhanced the response to fludarabine. In conclusion, bone marrow microenvironment modulates the PI3-K/Akt/PTEN cascade and prevents apoptosis of CLL cells. Combined inhibition of PI3-K/Akt and recovery of PTEN activity may represent a novel therapeutic concept for CLL. |
Databáze: | OpenAIRE |
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