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MEK inhibitors potentiate dexamethasone lethality in acute lymphoblastic leukemia cells through the pro-apoptotic molecule BIM.


ABSTRACT: Glucocorticoids (GCs) are common components of many chemotherapeutic regimens for lymphoid malignancies. GC-induced apoptosis involves an intrinsic mitochondria-dependent pathway. We and others have 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 and plays an essential role in Dex-induced apoptosis. 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 MEK inhibitors (PD184352 and PD98059) synergistically enhance Dex lethality in a variety of ALL cells and in two primary ALL specimens. Co-treatment with Dex and PD184352 results in BIM accumulation, pro-apoptotic BAX/BAK activation, and cytochrome c release from mitochondria. Down-regulation of BIM by short-hairpin RNA (shRNA) in ALL cells suppressed BAX/BAK activation, cytochrome c release, and cell death by Dex/PD184352 co-treatment. BIM accumulated by this treatment sequesters anti-apoptotic BCL-XLMCL-1, resulting in the release of BAK from these anti-apoptotic molecules. This study provides a rational foundation for future attempts to improve the activity of GCs with clinically relevant pharmacologic MEK inhibitors in the treatment of ALL and possibly other hematologic malignancies.

SUBMITTER: Rambal AA 

PROVIDER: S-EPMC2761998 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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MEK inhibitors potentiate dexamethasone lethality in acute lymphoblastic leukemia cells through the pro-apoptotic molecule BIM.

Rambal A A AA   Panaguiton Z L G ZL   Kramer L L   Grant S S   Harada H H  

Leukemia 20090430 10


Glucocorticoids (GCs) are common components of many chemotherapeutic regimens for lymphoid malignancies. GC-induced apoptosis involves an intrinsic mitochondria-dependent pathway. We and others have 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 and plays an essential role in Dex-induced apoptosis. Furthermore, BIM is inactivated by extracellular signal-regul  ...[more]

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