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

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.

[1]  L. Hou,et al.  Inhibition of KIF14 Suppresses Tumor Cell Growth and Promotes Apoptosis in Human Glioblastoma , 2015, Cellular Physiology and Biochemistry.

[2]  D. Hallahan,et al.  Valproic acid enhances the efficacy of radiation therapy by protecting normal hippocampal neurons and sensitizing malignant glioblastoma cells , 2015, Oncotarget.

[3]  Steven J. M. Jones,et al.  Comprehensive, Integrative Genomic Analysis of Diffuse Lower-Grade Gliomas. , 2015, The New England journal of medicine.

[4]  Qing Liu,et al.  Anti-Cancer Effect of Metabotropic Glutamate Receptor 1 Inhibition in Human Glioma U87 Cells: Involvement of PI3K/Akt/mTOR Pathway , 2015, Cellular Physiology and Biochemistry.

[5]  Qing Liu,et al.  Neuroprotective and anti-apoptotic effects of valproic acid on adult rat cerebral cortex through ERK and Akt signaling pathway at acute phase of traumatic brain injury , 2014, Brain Research.

[6]  M. Taphoorn,et al.  Effect of valproic acid on seizure control and on survival in patients with glioblastoma multiforme. , 2013, Neuro-oncology.

[7]  W. Rzeski,et al.  Apoptosis induction in human glioblastoma multiforme T98G cells upon temozolomide and quercetin treatment , 2013, Tumor Biology.

[8]  R. Altman,et al.  Valproic acid pathway: pharmacokinetics and pharmacodynamics , 2013, Pharmacogenetics and genomics.

[9]  W. Yoon,et al.  Valproic Acid Downregulates the Expression of MGMT and Sensitizes Temozolomide-Resistant Glioma Cells , 2012, Journal of biomedicine & biotechnology.

[10]  Y. Kitagishi,et al.  PI3K/AKT/PTEN Signaling as a Molecular Target in Leukemia Angiogenesis , 2012, Advances in hematology.

[11]  A. Cole,et al.  Molecular Neuroscience Review Article Gsk3 as a Sensor Determining Cell Fate in the Brain , 2022 .

[12]  Rebecca SY Wong,et al.  Apoptosis in cancer: from pathogenesis to treatment , 2011, Journal of experimental & clinical cancer research : CR.

[13]  R. Stupp,et al.  Current concepts and management of glioblastoma , 2011, Annals of neurology.

[14]  Daniel J Brat,et al.  Temozolomide in the treatment of high-grade gliomas in children: a report from the Children's Oncology Group. , 2011, Neuro-oncology.

[15]  R. Hen,et al.  Implications of the Functional Integration of Adult-Born Hippocampal Neurons in Anxiety-Depression Disorders , 2010, The Neuroscientist : a review journal bringing neurobiology, neurology and psychiatry.

[16]  A. Merlo,et al.  GSK3β Regulates Differentiation and Growth Arrest in Glioblastoma , 2009, PloS one.

[17]  W. Young.  Review of Lithium Effects on Brain and Blood , 2009, Cell transplantation.

[18]  M. Taphoorn,et al.  Efficacy of anti-epileptic drugs in patients with gliomas and seizures , 2009, Journal of Neurology.

[19]  R. Mirimanoff,et al.  Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. , 2009, The Lancet. Oncology.

[20]  Jia Luo,et al.  Glycogen synthase kinase 3beta (GSK3beta) in tumorigenesis and cancer chemotherapy. , 2009, Cancer letters.

[21]  S. Baird,et al.  IAP-targeted therapies for cancer , 2008, Oncogene.

[22]  Santosh Kesari,et al.  Malignant gliomas in adults. , 2008, The New England journal of medicine.

[23]  F. van Leuven,et al.  Glycogen synthase kinase‐3β, or a link between amyloid and tau pathology? , 2008, Genes, brain, and behavior.

[24]  L. Chin,et al.  Malignant astrocytic glioma: genetics, biology, and paths to treatment. , 2007, Genes & development.

[25]  I. T. de Almeida,et al.  Valproic acid metabolites inhibit dihydrolipoyl dehydrogenase activity leading to impaired 2-oxoglutarate-driven oxidative phosphorylation. , 2007, Biochimica et biophysica acta.

[26]  D. Reardon,et al.  Molecularly targeted therapy for malignant glioma , 2007, Cancer.

[27]  E. Raymond,et al.  Lessons learned in the development of targeted therapy for malignant gliomas , 2007, Molecular Cancer Therapeutics.

[28]  J. Wolff,et al.  Valproic acid induces p21 and topoisomerase-II (α/β) expression and synergistically enhances etoposide cytotoxicity in human glioblastoma cell lines , 2007, Journal of Neuro-Oncology.

[29]  G. Rosenberg,et al.  The mechanisms of action of valproate in neuropsychiatric disorders: can we see the forest for the trees? , 2007, Cellular and Molecular Life Sciences.

[30]  D. Jonas,et al.  Valproic acid inhibits adhesion of vincristine- and cisplatin-resistant neuroblastoma tumour cells to endothelium , 2007, British Journal of Cancer.

[31]  M. Weller,et al.  Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine , 2007, Oncogene.

[32]  J. Wolff,et al.  Valproic acid induces p21 and topoisomerase-II (alpha/beta) expression and synergistically enhances etoposide cytotoxicity in human glioblastoma cell lines. , 2007, Journal of neuro-oncology.

[33]  Lorenzo Galluzzi,et al.  Mitochondrial membrane permeabilization in cell death. , 2007, Physiological reviews.

[34]  Z. Kostrouch,et al.  Valproic acid, a molecular lead to multiple regulatory pathways. , 2007, Folia biologica.

[35]  Jihong Chen,et al.  Valproic acid and butyrate induce apoptosis in human cancer cells through inhibition of gene expression of Akt/protein kinase B , 2006, Molecular Cancer.

[36]  A. Valentini,et al.  Valproic acid induces apoptosis in prostate carcinoma cell lines by activation of multiple death pathways , 2006, Anti-cancer drugs.

[37]  M. Carducci,et al.  Chronic administration of valproic acid inhibits prostate cancer cell growth in vitro and in vivo. , 2006, Cancer research.

[38]  H. Doerr,et al.  Valproic acid induces extracellular signal-regulated kinase 1/2 activation and inhibits apoptosis in endothelial cells , 2006, Cell Death and Differentiation.

[39]  J. Vávrová,et al.  Effect of valproic acid and antiapoptotic cytokines on differentiation and apoptosis induction of human leukemia cells. , 2006, General physiology and biophysics.

[40]  Y. Zhou,et al.  Glycogen synthase kinase-3 is a negative regulator of extracellular signal-regulated kinase , 2006, Oncogene.

[41]  R. Seger,et al.  The extracellular signal-regulated kinase: Multiple substrates regulate diverse cellular functions , 2006, Growth factors.

[42]  C. Pérez-Plasencia,et al.  Antineoplastic effects of the DNA methylation inhibitor hydralazine and the histone deacetylase inhibitor valproic acid in cancer cell lines , 2006, Cancer Cell International.

[43]  Q. Duh,et al.  Valproic acid inhibits growth, induces apoptosis, and modulates apoptosis-regulatory and differentiation gene expression in human thyroid cancer cells. , 2005, Surgery.

[44]  C. Lau,et al.  Valproic acid induces growth arrest, apoptosis, and senescence in medulloblastomas by increasing histone hyperacetylation and regulating expression of p21Cip1, CDK4, and CMYC , 2005, Molecular Cancer Therapeutics.

[45]  H. Manji,et al.  Glycogen Synthase Kinase-3: a Putative Molecular Target for Lithium Mimetic Drugs , 2005, Neuropsychopharmacology.

[46]  S. Purgato,et al.  p21Waf1/Cip1 is a common target induced by short-chain fatty acid HDAC inhibitors (valproic acid, tributyrin and sodium butyrate) in neuroblastoma cells. , 2005, Oncology reports.

[47]  P. Kleihues,et al.  Population-based studies on incidence, survival rates, and genetic alterations in astrocytic and oligodendroglial gliomas. , 2005, Journal of neuropathology and experimental neurology.

[48]  C. Bowden,et al.  Valproate in bipolar disorder: 2000 onwards , 2005, Acta psychiatrica Scandinavica. Supplementum.

[49]  Martin J. van den Bent,et al.  Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. , 2005, The New England journal of medicine.

[50]  R. Mirimanoff,et al.  MGMT gene silencing and benefit from temozolomide in glioblastoma. , 2005, The New England journal of medicine.

[51]  O. Bosco,et al.  Valproic acid induces apoptosis and cell cycle arrest in poorly differentiated thyroid cancer cells. , 2005, The Journal of clinical endocrinology and metabolism.

[52]  J. Davie,et al.  The Ras-MAPK signal transduction pathway, cancer and chromatin remodeling. , 2005, Biochemistry and cell biology = Biochimie et biologie cellulaire.

[53]  M. Michaelis,et al.  Valproic acid and interferon-α synergistically inhibit neuroblastoma cell growth in vitro and in vivo , 2004 .

[54]  S. Fulda,et al.  Targeting apoptosis pathways in cancer therapy. , 2004, Current cancer drug targets.

[55]  O. Legrand,et al.  Valproic acid inhibits proliferation and induces apoptosis in acute myeloid leukemia cells expressing P-gp and MRP1 , 2004, Leukemia.

[56]  I. Germano,et al.  Role of autophagy in temozolomide-induced cytotoxicity for malignant glioma cells , 2004, Cell Death and Differentiation.

[57]  R. Busse,et al.  Valproic acid inhibits angiogenesis in vitro and in vivo. , 2004, Molecular pharmacology.

[58]  S. Korsmeyer,et al.  Cell Death Critical Control Points , 2004, Cell.

[59]  M. Michaelis,et al.  Valproic acid and interferon-alpha synergistically inhibit neuroblastoma cell growth in vitro and in vivo. , 2004, International journal of oncology.

[60]  H. Manji,et al.  The Role of the Extracellular Signal-Regulated Kinase Signaling Pathway in Mood Modulation , 2003, The Journal of Neuroscience.

[61]  Ping Zhu,et al.  The histone deacetylase inhibitor valproic acid selectively induces proteasomal degradation of HDAC2 , 2003, The EMBO journal.

[62]  K. Sano,et al.  Valproic acid induces apoptosis in human leukemia cells by stimulating both caspase-dependent and -independent apoptotic signaling pathways. , 2002, Leukemia research.

[63]  Arnab Chakravarti,et al.  Insulin-like growth factor receptor I mediates resistance to anti-epidermal growth factor receptor therapy in primary human glioblastoma cells through continued activation of phosphoinositide 3-kinase signaling. , 2002, Cancer research.

[64]  Ping Zhu,et al.  Valproic acid defines a novel class of HDAC inhibitors inducing differentiation of transformed cells , 2001, The EMBO journal.

[65]  M. Guenther,et al.  Histone Deacetylase Is a Direct Target of Valproic Acid, a Potent Anticonvulsant, Mood Stabilizer, and Teratogen* , 2001, The Journal of Biological Chemistry.

[66]  L. Recht,et al.  Practice parameter: Anticonvulsant prophylaxis in patients with newly diagnosed brain tumors , 2000, Neurology.

[67]  H. Manji,et al.  The Mood‐Stabilizing Agent Valproate Inhibits the Activity of Glycogen Synthase Kinase‐3 , 2000, Journal of neurochemistry.

[68]  P. Cohen,et al.  Role of protein kinase B and the MAP kinase cascade in mediating the EGF‐dependent inhibition of glycogen synthase kinase 3 in Swiss 3T3 cells 1 , 1999 .

[69]  P. Cohen,et al.  Role of protein kinase B and the MAP kinase cascade in mediating the EGF-dependent inhibition of glycogen synthase kinase 3 in Swiss 3T3 cells. , 1999, FEBS letters.

[70]  J. Činátl,et al.  Valproic acid inhibits proliferation and changes expression of CD44 and CD56 of malignant glioma cells in vitro. , 1998, Anticancer research.

[71]  C. Regan,et al.  Valproic acid suppresses G1 phase-dependent sialylation of a 65 kDa glycoprotein in the C6glioma cell cycle , 1997, International Journal of Developmental Neuroscience.

[72]  H. Doerr,et al.  Antitumor activity of sodium valproate in cultures of human neuroblastoma cells , 1996, Anti-cancer drugs.

[73]  P. Cohen,et al.  Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B , 1995, Nature.

[74]  J. Woodgett,et al.  Mitogen inactivation of glycogen synthase kinase-3 beta in intact cells via serine 9 phosphorylation. , 1994, The Biochemical journal.