Please use this identifier to cite or link to this item:
Title: Down-regulation of Mcl-1 potentiates HDACi-mediated apoptosis in leukemic cells.
Authors: Inoue, Satoshi
Walewska, Renata J.
Dyer, Martin J. S.
Cohen, Gerald M.
First Published: 31-Jan-2008
Publisher: Nature Publishing.
Citation: Leukemia, 2008, 22 (4), pp. 819-825.
Abstract: Mcl-1 is an anti-apoptotic Bcl-2 family member, whose degradation is supposedly required for induction of apoptosis. However, histone deacetylase inhibitors (HDACi) induce apoptosis primarily through the Bak/Mcl-1/Noxa and Bim pathways without decreasing Mcl-1. To investigate this discrepancy, we examined the role of Mcl-1 on HDACi-mediated apoptosis. Inhibition of either Class I or Class II HDAC by selective HDACi caused an upregulation of Mcl-1 mRNA and protein. Down-regulation of Mcl-1 by three structurally unrelated cyclin dependent kinase inhibitors potentiated HDACi-mediated apoptosis in primary chronic lymphocytic leukemic (CLL) cells and K562 cells. Sensitivity to HDACi-induced apoptosis was increased ~10-fold by the cyclin dependent kinase inhibitors. Nanomolar concentrations of HDACi, ~300-fold lower than required to induce apoptosis alone, sensitized cells to TRAIL, emphasizing that the mechanism(s) whereby HDACi induce apoptosis is clearly distinct from those by which they sensitize to TRAIL. Furthermore knockdown of Mcl-1 potentiated HDACi-mediated apoptosis in K562 cells. Thus HDACi-mediated Mcl-1 upregulation plays an important anti-apoptotic regulatory role in limiting the efficacy of HDACi-induced apoptosis, which can be overcome by combination with an agent that down-regulates Mcl-1. Thus a clinical trial in some cancers is warranted using a combination of an HDACi with agents that down-regulate Mcl-1.
DOI Link: 10.1038/leu.2008.1
ISSN: 0887-6924
Type: Article
Rights: This is the author’s final draft of the paper published as Leukemia, 2008, 22 (4), pp. 819-825. The final published version is available at, Doi: 10.1038/leu.2008.1
Appears in Collections:Published Articles, MRC Toxicology Unit

Files in This Item:
File Description SizeFormat 
Resubmitted manuscript & Figs 1-4 pdf Dec 17.pdf8.18 MBAdobe PDFView/Open

Items in LRA are protected by copyright, with all rights reserved, unless otherwise indicated.