Targeted activation of PKA and Epac promotes glioblastoma regression in vitro

• Published in: Molecular and clinical oncology Vol. 1; no. 2; pp. 281 - 285
• Main Authors: SUGIMOTO, NAOTOSHI, MIWA, SHINJI, TSUCHIYA, HIROYUKI, HITOMI, YOSHIAKI, NAKAMURA, HIROYUKI, YACHIE, AKIHIRO, KOIZUMI, SHOICHI
• Format: Journal Article
• Language: English
• Published: England D.A. Spandidos 01.03.2013; Spandidos Publications UK Ltd
• Subjects: Bone cancer; Brain cancer; Cell growth; cyclic adenosine monophosphate; exchange protein activated by cyclic adenosine monophosphate; glioblastoma; Kinases; mitogen-activated protein kinase; Oncology; Phosphorylation; protein kinase A; Proteins; Signal transduction; Statistical analysis; Studies; Tumors; Variance analysis; United States > US; Japan; mitogen-activated protein kinase; exchange protein activated by cyclic adenosine monophosphate; glioblastoma; cyclic adenosine monophosphate; protein kinase A
• DOI: 10.3892/mco.2013.65
• ISSN: 2049-9450

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.