Role of phosphodiesterase 2 in growth and invasion of human malignant melanoma cells

Cyclic nucleotide phosphodiesterases (PDEs) regulate the intracellular concentrations and effects of adenosine 3′,5′-cyclic monophosphate (cAMP) and guanosine 3′,5′-cyclic monophosphate (cGMP). The role of PDEs in malignant tumor cells is still uncertain. The role of PDEs, especially PDE2, in human...

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Published in:	Cellular signalling 2014-09, Vol.26 (9), p.1807-1817
Main Authors:	Hiramoto, Kenichi, Murata, Taku, Shimizu, Kasumi, Morita, Hiroshi, Inui, Madoka, Manganiello, Vincent C., Tagawa, Toshiro, Arai, Naoya
Format:	Article
Language:	eng
Subjects:	8-Bromo Cyclic Adenosine Monophosphate - pharmacology Adenine - analogs & derivatives Adenine - pharmacology Adenines Biotechnology Cell growth Cell Line, Tumor Cell Movement - drug effects Cell Proliferation - drug effects Cyclic AMP Cyclic AMP - metabolism Cyclic AMP-Dependent Protein Kinases - antagonists & inhibitors Cyclic AMP-Dependent Protein Kinases - metabolism Cyclic GMP - analogs & derivatives Cyclic GMP - pharmacology Cyclic Nucleotide Phosphodiesterases, Type 2 - antagonists & inhibitors Cyclic Nucleotide Phosphodiesterases, Type 2 - genetics Cyclic Nucleotide Phosphodiesterases, Type 2 - metabolism Human Human malignant melanoma Humans Inhibitors Invasion Melanoma - enzymology Melanoma - metabolism Melanoma - pathology Nucleotides Partial differential equations Phosphodiesterase 2 Retarding RNA Interference RNA, Small Interfering - metabolism Rolipram - pharmacology Tumors
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Summary:	Cyclic nucleotide phosphodiesterases (PDEs) regulate the intracellular concentrations and effects of adenosine 3′,5′-cyclic monophosphate (cAMP) and guanosine 3′,5′-cyclic monophosphate (cGMP). The role of PDEs in malignant tumor cells is still uncertain. The role of PDEs, especially PDE2, in human malignant melanoma PMP cell line was examined in this study. In PMP cells, 8-bromo-cAMP, a cAMP analog, inhibited cell growth and invasion. However, 8-bromo-cGMP, a cGMP analog, had little or no effect. PDE2 and PDE4, but not PDE3, were expressed in PMP cells. Growth and invasion of PMP cells were inhibited by erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), a specific PDE2 inhibitor, but not by rolipram, a specific PDE4 inhibitor. Moreover, cell growth and invasion were inhibited by transfection of small interfering RNAs (siRNAs) specific for PDE2A and a catalytically-dead mutant of PDE2A. After treating cells with EHNA or rolipram, intracellular cAMP concentrations were increased. Growth and invasion were stimulated by PKA14-22, a PKA inhibitor, and inhibited by N6-benzoyl-c AMP, a PKA specific cAMP analog, whereas 8-(4-chlorophenylthio)-2′-O-methyl-cAMP, an Epac specific cAMP analog, did not. Invasion, but not growth, was stimulated by A-kinase anchor protein (AKAP) St-Ht31 inhibitory peptide. Based on these results, PDE2 appears to play an important role in growth and invasion of the human malignant melanoma PMP cell line. Selectively suppressing PDE2 might possibly inhibit growth and invasion of other malignant tumor cell lines. •The role of PDEs, especially PDE2, in malignant tumor cells is still uncertain.•Inhibition of PDE2 reduces cell growth and invasion of PMP cells.•PKA signaling pathways are involved in growth and invasion of PMP cells.•PDE2 serves as a new therapeutic target for malignant melanoma.
ISSN:	0898-6568 1873-3913