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Valproic acid
and butyrate induce apoptosis in human cancer cells through inhibition
of gene expression of Akt/protein kinase B
Jihong Chen,
Feras M Ghazawi, Wafae Bakkar and Qiao Li*
Department of Pathology
and Laboratory Medicine, Faculty of Medicine, University of Ottawa,
451 Smyth Road, Room 4155, Ottawa, Ontario, Canada K1H8M5 -- *Corresponding
author: Qiao Li, Department of Pathology and Laboratory Medicine,
University of Ottawa, 451 Smyth Road, Room 4155, Ottawa, Ontario,
Canada K1H 8M5, Phone: (613) 798 5555 ext. 13454, Fax: (613) 761 5036,
Email: qli@ohri.ca -- Submission date 15
August 2006, Acceptance date 11 December 2006, Publication date 11
December 2006.
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Background.
In eukaryotic cells, the genomic DNA is packed with histones to
form the nucleosome and chromatin structure.
Reversible acetylation of the histone
tails plays an important role in the control of specific gene
expression.
Mounting evidence has established that
histone deacetylase inhibitors selectively induce cellular
differentiation, growth arrest and apoptosis in variety of cancer
cells, making them a promising class of anticancer drugs.
However, the molecular mechanisms of the
anti-cancer effects of these inhibitors have yet to be understood.
Results.
Here, we report that a key determinant for the susceptibility
of cancer cells to histone deacetylase inhibitors is their ability to
maintain cellular Akt activity in response to the treatment.
Also known as protein kinase B, Akt is an
essential pro-survival factor in cell proliferation and is often
deregulated during tumorigenesis.
We show that histone deacetylase
inhibitors, such as valproic acid and butyrate, impede Akt1 and Akt2
expression, which leads to Akt deactivation and apoptotic cell
death.
In addition, valproic acid and butyrate
induce apoptosis through the caspase-dependent pathway.
The activity of caspase-9 is robustly
activated upon valproic acid or butyrate treatment.
Constitutively active Akt is able to block
the caspase activation and rescues cells from butyrate-induced
apoptotic cell death.
Conclusions.
Our study demonstrates that although the primary target of
histone deacetylase inhibitors is transcription, it is the capacity of
cells to maintain cellular survival networks that determines their
fate of survival.
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