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

Abstract

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 N(6)-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.

• Authors: Kenichi Hiramoto, Taku Murata, Kasumi Shimizu, Hiroshi Morita, Madoka Inui, Vincent C Manganiello, Toshiro Tagawa, Naoya Arai
• Journal: Cellular signalling (Cell Signal) Vol. 26 Issue 9 Pg. 1807-17 (Sep 2014) ISSN: 1873-3913 [Electronic] England
• PMID: 24705027 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2014. Published by Elsevier Inc.

Chemical References

• RNA, Small Interfering
• 8-Bromo Cyclic Adenosine Monophosphate
• 8-bromocyclic GMP
• 9-(2-hydroxy-3-nonyl)adenine
• Cyclic AMP
• Cyclic AMP-Dependent Protein Kinases
• Cyclic Nucleotide Phosphodiesterases, Type 2
• PDE2A protein, human
• Cyclic GMP
• Adenine
• Rolipram

Topics

• 8-Bromo Cyclic Adenosine Monophosphate (pharmacology)
• Adenine (analogs & derivatives, pharmacology)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Cyclic AMP (metabolism)
• Cyclic AMP-Dependent Protein Kinases (antagonists & inhibitors, metabolism)
• Cyclic GMP (analogs & derivatives, pharmacology)
• Cyclic Nucleotide Phosphodiesterases, Type 2 (antagonists & inhibitors, genetics, metabolism)
• Humans
• Melanoma (enzymology, metabolism, pathology)
• RNA Interference
• RNA, Small Interfering (metabolism)
• Rolipram (pharmacology)