These tools will no longer be maintained as of December 31, 2024. Archived website can be found here. PubMed4Hh GitHub repository can be found here. Contact NLM Customer Service if you have questions.


Pubmed for Handhelds

PUBMED FOR HANDHELDS

Search MEDLINE/PubMed

  • Title: MEK1/2 inhibitors potentiate UCN-01 lethality in human multiple myeloma cells through a Bim-dependent mechanism.
    Author: Pei XY, Dai Y, Tenorio S, Lu J, Harada H, Dent P, Grant S.
    Journal: Blood; 2007 Sep 15; 110(6):2092-101. PubMed ID: 17540843.
    Abstract:
    The role of Bim in synergistic interactions between UCN-01 and MEK1/2 inhibitors in human multiple myeloma cells was investigated. Exposure of U266 or RPMI8226 cells to UCN-01 resulted in ERK1/2 activation-associated Bim(EL) phosphorylation/down-regulation, events abrogated by MEK1/2 inhibitors. Enforced activation of ERK1/2 by transfection with constitutively active MEK1 diminished the capacity of PD98059 but not PD184352 to block UCN-01-mediated Bim(EL) phosphorylation and to potentiate apoptosis. Cotreatment with MEK1/2 inhibitors increased the association of Bim(EL) with both Bcl-2 and Bcl-x(L) in UCN-01-treated cells, leading to Bax/Bak conformational change and Bax mitochondrial translocation. Down-regulation of Bim(EL) by shRNA substantially diminished UCN-01/MEK inhibitor-mediated Bax/Bak activation and apoptosis. Furthermore, transfection of cells with S65A Bim, a mutant resistant to UCN-01-mediated phosphorylation, significantly sensitized cells to UCN-01 lethality. Conversely, ectopic expression of either Bcl-2 or Bcl-x(L) did not alter UCN-01/MEK1/2 inhibitor-mediated modifications in Bim(EL) phosphorylation but largely prevented cell death. Finally, IL-6 or IGF-1 failed to prevent MEK1/2 inhibitors from blocking UCN-01-induced Bim(EL) phosphorylation/degradation or cell death. Collectively, these findings argue that UCN-01-mediated ERK1/2 activation leads to Bim(EL) phosphorylation/inactivation, resulting in cytoprotection, and that interference with these events by MEK1/2 inhibitors plays a critical role in synergistic induction of apoptosis by these agents.
    [Abstract] [Full Text] [Related] [New Search]