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191 Sensitizing Hemopoietic Malignant Cells to Glucocorticoid Induced Apoptosis by PK Inhibitors

Kfir, S; Vogt-Sionov, R; Spokoini, R; Cohen, O; Yefenof, E

JAIDS Journal of Acquired Immune Deficiency Syndromes: April 2011 - Volume 56 - Issue - p 80
doi: 10.1097/01.qai.0000397373.16320.ff

The Lautenberg Center for General and Tumor Immunology, The Hebrew University-Hadassah Medical School, Jerusalem, Israel

Glucocorticoids (GCs) are widely used in the therapy of lymphomas and lymphoblastic leukemias owing to their apoptogenic effects on these cancerous cells. A major impediment of GC-based therapy is the gradual acquisition of apoptotic resistance to GC treatment. Also, certain lymphomas and leukemias are a priori resistant to GC. Therefore, a desirable goal is to develop therapeutic strategies that confer GC-sensitivity on otherwise GC-resistant cells. We observed that the broad-acting protein kinase (PK) inhibitor Staurosporine (STS) confers GC-sensitivity on several GC-resistant T and B lymphoma cells. GC-resistant T lymphoma cells express elevated levels of the anti-apoptotic proteins Bcl-2 or Bcl-XL. Transfection with Bcl-2 or Bcl-XL in sensitive cells confers resistance to GC-induced apoptosis. Surprisingly, STS overcomes the anti-apoptotic properties of Bcl-2 but not of Bcl-XL. STS acts at several levels. It induces the expression of the pro-apoptotic Nur77 orphan receptor, which overcomes the anti-apoptotic effects of Bcl-2. STS also leads to phosphorylation of Bim by an ERK-dependent mechanism which results in Bim upregulation. In addition, STS inhibits PI3K/Akt, leading to the activation of GSK3. Inhibition of GSK3 by its specific inhibitor SB216763 or by overexpression of a dominant negative GSK3 attenuated the effect of STS. Our study demonstrates a central role for GSK3α, but not GSK3α, in promoting GC-induced apoptosis. We found that GSK3α is sequestered to the glucocorticoid receptor (GR) in the absence of ligand, but dissociates from the GR complex upon exposure to GC to promote apoptosis. GC-resistance in lymphoma cells can be relieved by inhibiting the PI3K-Akt survival pathway, which inactivates GSK3 by its phosphorylation. Notch1, a transcription factor frequently activated in T acute lymphoblastic leukemia(T-ALL), confers GC resistance through activation of Akt. Indeed, inhibition of Akt is effective in sensitizing T-ALL cells to GC induced apoptosis. Our data demonstrate that lymphoma and leukemia therapy can be significantly improved if GCs are combined with PK inhibitors that shift the cell's kinome in favor of apoptosis-prone phenotype.

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