title: Targeted activation of PKA and Epac promotes glioblastoma regressionin vitro.
abstract: Ras-p44/42 mitogen-activated protein kinase (MAPK) and Akt signaling are the key pathways involved in the promotion of glioblastoma formation. Notably, phosphodiesterase 4 (PDE4) is widely expressed in brain tumors and promotes their growth. PDE4 inhibitors have been reported to suppress glioblastoma growthin vitroandin vivo. The mechanisms underlying these actions, however, have yet to be elucidated. The aim of this study was to investigate whether intracellular cyclic adenosine monophosphate (cAMP) was able to suppress the Ras-p44/42 MAPK signaling pathway via protein kinase A (PKA) and exchange protein directly activated by cAMP (Epac) in U87MG human malignant glioma cells. Forskolin, an activator of adenylate cyclase, inhibited cell growth and the phosphorylation of p44/42 MAPK in U87MG cells, whereas the non-hydrolyzable cAMP analog 8-bromoadenosine 3',5'-cAMP (8-Br-cAMP) considerably suppressed cell growth and phosphorylation of p44/42 MAPK. The inhibitory effects of forskolin were partially prevented by the PKA inhibitor H89. The Epac-selective agonist 8-(4-chlorophenylthio)-2'-O-methyladenosine cAMP (8-CPT-cAMP) inhibited phosphorylation of p44/42 MAPK. These findings suggest that PKA and Epac are involved in the effect of intracellular cAMP on the Ras-p44/42 MAPK signaling pathway.
authors.affiliation: Departments of Physiology, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan.
authors.forename: Naotoshi
authors.initials: N
authors.lastname: Sugimoto
authors.affiliation: Orthopedic Surgery, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan.
authors.forename: Shinji
authors.initials: S
authors.lastname: Miwa
authors.affiliation: Orthopedic Surgery, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsuchiya
authors.affiliation: Public Health, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan.
authors.forename: Yoshiaki
authors.initials: Y
authors.lastname: Hitomi
authors.affiliation: Public Health, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Nakamura
authors.affiliation: Pediatrics, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Yachie
authors.affiliation: United Graduate School of Child Development, Kanazawa University, Kanazawa, Ishikawa 920-8640, Japan.
authors.forename: Shoichi
authors.initials: S
authors.lastname: Koizumi
keywords: cyclic adenosine monophosphate; exchange protein activated by cyclic adenosine monophosphate; glioblastoma; mitogen-activated protein kinase; protein kinase A