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MEK inhibitors potentiate dexamethasone lethality in acute lymphoblastic leukemia cells through the pro-apoptotic molecule BIM.
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- Author(s): Rambal, A. A.1; Panaguiton, Z. L. G.1; Kramer, L.1; Grant, S.1; Harada, H.1
- Source:
Leukemia (08876924). Oct2009, Vol. 23 Issue 10, p1744-1754. 11p. 1 Diagram, 6 Graphs.- Subject Terms:
*GLUCOCORTICOIDS; *APOPTOSIS; *MITOCHONDRIA; *LYMPHOBLASTIC leukemia; *PHOSPHORYLATION; *PROTEIN metabolism; *DEXAMETHASONE; *BENZAMIDE; *CELL lines; *CELL physiology; *CELLS; *DRUG synergism; *FLAVONOIDS; *MEMBRANE proteins; *MOLECULAR structure; *PHOSPHOTRANSFERASES; *RESEARCH funding; *TRANSFERASES; *WESTERN immunoblotting; *PRECIPITIN tests; *CHEMICAL inhibitors - Source:
- Additional Information
- 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. [ABSTRACT FROM AUTHOR]
- Abstract: Copyright of Leukemia (08876924) is the property of Springer Nature and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)
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