title: Valproic acid inhibits the proliferation of SHSY5Y neuroblastoma cancer cells by downregulating URG4/URGCP and CCND1 gene expression.
abstract: Valproic acid (VPA), used for the treatment of epilepsy and bipolar disorder, regulates several signaling pathways in brain cells. The up-regulated gene 4 (URG4/URGCP) is a novel gene located on 7p13. URG4/URGCP stimulates cyclin D1 (CCND1) mRNA expression, and URG4/URGCP silencing diminishes CCND1 mRNA expression in HepG2 cells. This study was performed to investigate the anti-cancer mechanism of action of VPA by analyzing the expression of novel gene URG4/URGCP, CCND1, p21, p53, p65 (RelA), Bax, and Bcl-2 in SHSY5Y neuroblastoma (NB) cancer cells. Cytotoxic effects of VPA in SHSY5Y were noticed in time and dose dependent manner with the IC50 doses within the range of 0.5-10 mM. IC50 doses in the SHSY5Y were detected as 7.5 mM. Expression profiles were determined by semi quantitative RT-PCR and URG4/URGCP protein change by western blot analysis. Our results suggest that VPA induces cell cycle arrest in SHSY5Y due to the decrease in URG4/URGCP, CCND1 gene expression and the increase in p65. To conclude, VPA may be a prospective agent for the treatment of NB as a single agent or in combination with other drugs. Thus, more studies should be designed to find a safe dose with the best effects of VPA.
authors.affiliation: Department of Medical Biology, Pamukkale University School of Medicine, Kınıklı Kampüsü Morfoloji Binasi Kat:3 Kınıklı, Denizli, Turkey, yavuzdodurga@gmail.com.
authors.forename: Yavuz
authors.initials: Y
authors.lastname: Dodurga
authors.forename: Gulsah
authors.initials: G
authors.lastname: Gundogdu
authors.forename: Volkan
authors.initials: V
authors.lastname: Tekin
authors.forename: Tugba
authors.initials: T
authors.lastname: Koc
authors.forename: N Lale
authors.initials: NL
authors.lastname: Satiroglu-Tufan
authors.forename: Gulseren
authors.initials: G
authors.lastname: Bagci
authors.forename: Vural
authors.initials: V
authors.lastname: Kucukatay
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D019938:Cyclin D1 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D014635:Valproic Acid / Q000494:pharmacology*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; C530104:CCND1 protein, human; D009363:Neoplasm Proteins; C498143:RELA protein, human; D051996:Transcription Factor RelA; C470990:URGCP protein, human; D019938:Cyclin D1; D014635:Valproic Acid