Phosphodiesterase inhibitors control A172 human glioblastoma cell death through cAMP-mediated activation of protein kinase A and Epac1/Rap1 pathways
- Authors
- Moon, Eun-Yi; Lee, Geun-Hee; Lee, Myung-Shik; Kim, Hwan-Mook; Lee, Jae-Wook
- Issue Date
- 27-Feb-2012
- Publisher
- PERGAMON-ELSEVIER SCIENCE LTD
- Keywords
- Rolipram; PDE; Glioblastoma; cAMP; PKA; Epac1; Rap1
- Citation
- LIFE SCIENCES, v.90, no.9-10, pp.373 - 380
- Journal Title
- LIFE SCIENCES
- Volume
- 90
- Number
- 9-10
- Start Page
- 373
- End Page
- 380
- URI
- https://scholarworks.bwise.kr/gachon/handle/2020.sw.gachon/16575
- DOI
- 10.1016/j.lfs.2011.12.010
- ISSN
- 0024-3205
- Abstract
- Aims: We investigated whether cAMP-mediated protein kinase A(PKA) and Epac1/Rap1 pathways differentially affect brain tumor cell death using 4-(3-cyclopentyloxy-4-methoxyphenyl)-2-pyrrolidone(rolipram), specific phosphodiesterase type IV(PDE IV) inhibitor. Main methods: A172 and U87MG human glioblastoma cells were used. Percentage of cell survival was determined by MTT assay. PKA and Epac1/Rap1 activation was determined by western blotting and pull-down assay, respectively. Cell cycle and hypodiploid cell formation were assessed by flow cytometry analysis. Key findings: Non-specific PDE inhibitors, isobutylmethylxanthine(IBMX) and theophylline reduce survival percentage of A172 and U87MG cells. The expression of PDE4A and PDE4B was detected in A172 and U87MG cells. Rolipram-treated A172 or U87MG cell survival was lower in the presence of forskolin, adenylate cyclase activator, than that in its absence. Co-treatment with rolipram and forskolin also enhanced CREB phosphorylation on serine 133 that was inhibited by H-89, PKA inhibitor and cAMP-responsive guanine nucleotide exchange factor 1(Epac1), a Rap GDP exchange factor-mediated Rap1 activity in A172 cells. When A172 cells were treated with cell-permeable dibutyryl-cAMP(dbcAMP), PKA activator or 8-(4-chlorophenylthio)-2'-O-methyladenosine-3',5'-cyclic monophosphate(CPT), Epac1 activator, basal level of cell death was increased and cell cycle was arrested at the phase of G2/M. Rolipram-induced A172 cell death was also increased by the co-treatment with dbcAMP or CPT, but it was inhibited by the pre-treatment with H-89. Significance: These findings demonstrate that PKA and Epac1/Rap1 pathways could cooperatively play a role in rolipram-induced brain tumor cell death. It suggests that rolipram might regulate glioblastoma cell density through dual pathways of PKA- and Epac1/Rap1 -mediated cell death and cell cycle arrest. Crown Copyright (C) 2011 Published by Elsevier Inc. All rights reserved.
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