Targeted activation of PKA and Epac promotes glioblastoma regression in vitro

Sugimoto,Naotoshi; Miwa,Shinji; Tsuchiya,Hiroyuki; Hitomi,Yoshiaki; Nakamura,Hiroyuki; Yachie,Akihiro; Koizumi,Shoichi

doi:10.3892/mco.2013.65

Targeted activation of PKA and Epac promotes glioblastoma regression in vitro

Authors:
- Naotoshi Sugimoto
- Shinji Miwa
- Hiroyuki Tsuchiya
- Yoshiaki Hitomi
- Hiroyuki Nakamura
- Akihiro Yachie
- Shoichi Koizumi
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Affiliations: Department of Physiology, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8640, Japan, Department of Orthopedic Surgery, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8640, Japan, Department of Public Health, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8640, Japan, Department of Pediatrics, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8640, Japan, United Graduate School of Child Development, Kanazawa University, Kanazawa, Ishikawa 920‑8640, Japan
Published online on: January 14, 2013 https://doi.org/10.3892/mco.2013.65
Pages: 281-285

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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 growth in vitro and in 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.

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