Valproic Acid Promotes Human Glioma U87 Cells Apoptosis and Inhibits Glycogen Synthase Kinase-3β Through ERK/Akt Signaling

Abstract

Background: Valproic acid (VPA), an established antiepileptic drug, was assessed for antitumor activity, including its effects on glioblastoma, but its role has not been determined. Methods: In the present study, we investigated VPA-induced apoptosis effects on human U87 cells by cell viability, lactate dehydrogenase (LDH) release, TUNEL/Hoechst staining and flow cytometric in vitro, then we further explored the underlying molecular mechanisms using the selective antagonists PD98059, LY294002 and SB216763. Results: The data showed that VPA dose-dependent induction of glioma U87 cells to undergo apoptosis through the mitochondria-dependent pathway in vitro. VPA activated the ERK/Akt pathways by increasing their protein phosphorylation and in turn inhibited GKS3β activation by the induction of GKS3β phosphorylation. However, the MAPK inhibitor PD98059 and/or PI3K inhibitor LY294002 were able to antagonize the effects of VPA by abolishing ERK/Akt activations and cancelling GSK3β suppression, thus it impaired VPA apoptosis-inducing effects on glioma cells. Furthermore, the GSK3β inhibitor SB216763 caused a strong suppression of GSK3β activity, which showed similar effects of VPA on regulation of protein expression and apoptosis. Conclusion: These findings suggest that GSK3β may be the central hub for VPA-induced apoptosis and VPA can be further evaluated as a novel agent for glioma therapy.

Cellular Effects of the Antiepileptic Drug Valproic Acid in Glioblastoma

“…These results were unexpected in light of the reported chromatin remodeling action of VPA [18, 48-50] and contradictory to previous in vitro studies [10-15, 17, 48, 51, 52] which clearly show VPA-induced cell death or radio- or chemosensitization in cancer cells including glioma. Unlike the present work, VPA concentrations of 1-5 mM [52], 1.5-2 mM [10], 1-5 mM [51], 2.5-5 mM [11], 1.5-3 mM [12], 1-15 mM [13], 2-16 mM [14], 7.5 mM [18], 2 mM [19], 5-20 mM [53], 1-10 mM [21], or 4.8 mM [22] were applied in these studies.…”

“…Beyond radio- and temozolomide sensitization, VPA-mediated histone hyperacetylation and DNA demethylation are associated with changes in cell morphology, decrease cell viability and increase apoptosis rates [14, 19, 21, 22]. Moreover, VPA treatment of glioma cells has been demonstrated to boost the adaptive immune response.…”

The Key Roles of GSK-3β in Regulating Mitochondrial Activity

“…GSK-3β activation is prior to initiation of the caspase cascade correlating to cell apoptosis [69]. GSK-3β is phosphorylated and negatively regulated by many signaling pathways, including PI3K/Akt, PKA, ERK, PKC, p90rsk, and p70S6K, which are involved in mediation of mitochondrial activity [70, 71]. GSK-3β is correlated with activation of caspase-2 and caspase-8, which can induce the cleavage of Bid and the release of cytochrome c , leading to mitochondrial dysfunction and apoptosis.…”

Fstl1 Promotes Glioma Growth Through the BMP4/Smad1/5/8 Signaling Pathway

“…Glioblastoma multiforme (GBM) is the most common and deadly brain tumor in adults, accounting for approximately 80% of malignant tumors affecting the central nervous system [1, 2]. Despite advances in standard therapy, including diagnostic methods and treatment strategies, the prognosis for patients with GBM remains poor, with an average survival time of 12–15 month after diagnosis [3-5].…”