Valproic acid inhibits cell size and cell proliferation by AMPK-mediated mTOR signaling pathway in JEG-3 cells

Title
Valproic acid inhibits cell size and cell proliferation by AMPK-mediated mTOR signaling pathway in JEG-3 cells
Authors
김연정이지나송미경한태준류재천
Keywords
Valproic acid; placenta cell line (JEG-3); AMPK; mTOR signaling; teratogenicity; transcriptomics
Issue Date
2013-09
Publisher
BioChip Journal
Citation
VOL 7, NO 3, 267-277
Abstract
Valproic acid is commonly used to treat seizure disorders, bipolar disorder, migraine prophylaxis, and neuropathic pain. Despite its effectiveness and widespread use, valproic acid has been proven to exert considerable teratogenic potential, such as neural tube defects and malformations of the heart in both the humans and animals. However, the molecular mechanism of the teratogenic effects of valproic acid has not been fully elucidated. Because adverse effects in fetus by teratogens are obviously detectable only after birth and there are the limits of teratogenicity testing using rodents, such as thalidomide tragedy, new strategies for pre-determining teratogenic effects are required. Here, we try to elucidate the indirect teratogenicity of valproic acid in a human placenta-derived cell line (JEG-3) using a transcriptomic approach. In this study, using human whole genome oligonucleotide microarray, we identified 2,076 up- and 1,730 down-regulated genes which were changed more than 1.5-fold in JEG-3 cells exposed to valproic acid. Many of these genes have associations with lysosome, transport, tight junction, splicesome, cell cycle and mammalian target of rapamycin (mTOR)-signaling pathway. Among these, we focused on the adenosine monophosphate (AMP)-dependent kinase or AMP-activated kinase (AMPK)-mediated mTOR signaling pathway, and hypothesized that the negative control of mTOR signaling by AMPK might induce inhibition of the growth of JEG-3 cell exposed to valproic acid. First, flow cytometry analysis showed that valproic acid induced the inhibition of cell growth caused by G1 phase arrest. Second, the expression of genes related to mTOR signaling was changed. Using quantitative real-time RT-PCR data, it was confirmed that PTEN, PIK3CB, PIK3CD, PIK3R3, IRS2, and PRKAA2 (AMPKα2) were overexpressed, and that GβL and AKT1 were under-expressed in valproic acid treated JEG-3 cells compared to a control. We also confir
URI
http://pubs.kist.re.kr/handle/201004/46490
ISSN
19760280
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KIST Publication > Article
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