ROLE OF BCL-2 FAMILY MEMBERS TO PROMOTE GLUCOCORTICOID –INDUCED APOPTOSIS BY MEK INHIBITORS IN LEUKEMIC CELLS
Glucocorticoids (GC) are common components of many chemotherapeutic regimens for lymphoid malignancies. GC-induced apoptosis involves an intrinsic BCL-2 family-regulated pathway. It has been shown that BIM (BCL-2 interacting mediator of cell death), a BH3-only pro-apoptotic protein, is up-regulate...
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| Format: | Others |
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VCU Scholars Compass
2009
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| Online Access: | http://scholarscompass.vcu.edu/etd/1790 http://scholarscompass.vcu.edu/cgi/viewcontent.cgi?article=2789&context=etd |
| Summary: | Glucocorticoids (GC) are common components of many chemotherapeutic regimens for lymphoid malignancies. GC-induced apoptosis involves an intrinsic BCL-2 family-regulated pathway. It has been shown that BIM (BCL-2 interacting mediator of cell death), a BH3-only pro-apoptotic protein, is up-regulated by dexamethasone (Dex) treatment in acute lymphoblastic leukemia (ALL) cells. Furthermore, BIM is inactivated by extracellular signal-regulated kinase (ERK)-mediated phosphorylation. We therefore hypothesized co-treatment with Dex and MEK/ERK inhibitors would promote apoptosis in ALL cells through BIM up-regulation and activation. We show here that a MEK inhibitor, PD184352 synergistically enhances Dex lethality in CCRF-CEM (T-ALL) cells. Co-treatment with Dex and PD184352 results in BIM accumulation. Down-regulation of BIM by short-hairpin RNA in CCRF-CEM cells suppressed apoptosis by Dex/PD184352 co-treatment. In contrast, another BH3-only protein, BAD is dispensable. Thus, BIM is a critical molecule in this regimen, and targeting BIM by drugs combination could be effective on ALL and possibly other malignancies. |
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