Published in:
01-10-2007 | Original Paper
Pro-apoptotic activity of oncogenic H-Ras for histone deacetylase inhibitor to induce apoptosis of human cancer HT29 cells
Published in: Journal of Cancer Research and Clinical Oncology | Issue 10/2007
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Purpose
To verify the pro-apoptotic activity of oncogenic H-Ras in the increased susceptibility of human cancer cells to histone deacetylase inhibitor (HDACI).
Methods
The pro-apoptotic activity of oncogenic H-Ras(V12) was verified by its ability to increase susceptibility of human colorectal adenocarcinoma HT29 cells to HDACI for inducing apoptosis and growth inhibition, assayed by various methods. The mode of action of HDACI FR901228 was studied by its ability to modulate protein phosphorylation, acetylation, and expression levels in various signaling pathways, measured by Western blot analysis.
Results
Activation of caspase-3, -7, and -8, and serine protease by FR901228 was facilitated by oncogenic H-Ras to induce apoptosis. Expression of H-Ras(V12) changed the intrinsic modulation of Raf in cells responding to FR901228 treatment. Both p21
Cip1
and p27
Kip1
were induced in FR901228-treated cells arrested in either the G0/G1 or G2/M phase of the cell cycle. Deacetylation of FR901228-induced acetylation of core histones was accelerated by H-Ras(V12) in cells undergoing apoptosis.
Conclusion
Expression of H-Ras(V12) increased susceptibility of HT29 cells to HDACI FR901228 and Trichostatin A for inducing apoptosis. The pro-apoptotic activity of H-Ras(V12) responding to HDACI indicates a potential value of this new class of anticancer agents in treating Ras-related human cancers.