Cell type-specific anti-cancer properties of valproic acid: independent effects on HDAC activity and Erk1/2 phosphorylation.
BACKGROUND
The anti-epileptic drug valproic acid (VPA) has attracted attention as an anti-cancer agent.


METHODS
The present study investigated effects of VPA exposure on histone deacetylase (HDAC) inhibition, cell growth, cell speed, and the degree of Erk1/2 phosphorylation in 10 cell lines (BT4C, BT4Cn, U87MG, N2a, PC12-E2, CSML0, CSML100, HeLa, L929, Swiss 3T3).


RESULTS
VPA induced significant histone deacetylase (HDAC) inhibition in most of the cell lines, but the degree of inhibition was highly cell type-specific. Moreover, cell growth, motility and the degree of Erk1/2 phosphorylation were inhibited, activated, or unaffected by VPA in a cell type-specific manner. Importantly, no relationship was found between the effects of VPA on HDAC inhibition and changes in the degree of Erk1/2 phosphorylation, cell growth, or motility. In contrast, VPA-induced modulation of the MAPK pathway downstream of Ras but upstream of MEK (i.e., at the level of Raf) was important for changes in cell speed.


CONCLUSIONS
These results suggest that VPA can modulate the degree of Erk1/2 phosphorylation in a manner unrelated to HDAC inhibition and emphasize that changes in the degree of Erk1/2 phosphorylation are also important for the anti-cancer properties of VPA.
Gotfryd
Kamil
K
Protein Laboratory, Department of Neuroscience and Pharmacology, Faculty of Health Sciences, University of Copenhagen, Denmark.
Skladchikova
Galina
G
Lepekhin
Eugene A
EA
Berezin
Vladimir
V
Bock
Elisabeth
E
Walmod
Peter S
PS
D000107:Acetylation / Q000187:drug effects; D000818:Animals; D015153:Blotting, Western; D002448:Cell Adhesion / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006655:Histone Deacetylases / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D014635:Valproic Acid / Q000494:pharmacology*
D004791:Enzyme Inhibitors; D014635:Valproic Acid; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D006655:Histone Deacetylases