Biomedical papers, 2014 (vol. 158), issue 1

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2014, 158(1):039-043 | 10.5507/bp.2012.038

Valproate activates ERK signaling pathway in primary human hepatocytes

Michal Bitmana, Radim Vrzalb, Zdenek Dvorakb, Petr Paveka
a Department of Pharmacology and Toxicology, Faculty of Pharmacy in Hradec Kralove, Charles University in Prague, Heyrovskeho 1203, 500 05 Hradec Kralove, Czech Republic
b Department of Cell Biology and Genetics, Faculty of Science, Palacky University Olomouc, Slechtitelu 11, 783 71 Olomouc

Aim: Valproic acid (VPA) is a widely-used anticonvulsant and mood-stabilizing agent. VPA is also known to inhibit histone deacetylases (HDACs) affecting the expression of numerous genes.

Methods: In the present study, we examined the effect of VPA on the extracellular signal-related kinase (ERK, p42/p44) pathway (Ras-Raf-MEK-ERK) belonging to the mitogen-activated protein kinases (MAPKs) pathways in primary human hepatocytes. In the liver, the pathway is associated with progression of hepatocellular carcinoma.

Results: We found that VPA in a therapeutically relevant concentration (500 µM) activates the ERK pathway, as indicated by increased ERK Thr202/Tyr204 phosphorylation. Interestingly, a prototype HDAC inhibitor, trichostatin A, also activated ERK phosphorylation in primary human hepatocytes. These data suggest that HDAC inhibition might be the primary stimulus for ERK pathway activation in primary human hepatocytes. Notably, U0126, a MEK1 inhibitor, was ineffective in inhibiting ERK pathway activation, likely due to its metabolic deactivation in metabolically competent primary human hepatocytes.

Conclusion: We conclude that VPA activates the ERK pathway in primary human hepatocytes.

Keywords: valproic acid, ERK pathway, cellular signaling

Received: October 27, 2011; Accepted: March 28, 2012; Prepublished online: June 1, 2012; Published: April 1, 2014


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