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 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.
Department of Oral and Maxillofacial Surgery, Department of Clinical Sciences, Medical Life Science, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
Kenichi
K
Hiramoto
Department of Oral and Maxillofacial Surgery, Department of Clinical Sciences, Medical Life Science, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
Taku
T
Murata
Department of Oral and Maxillofacial Surgery, Department of Clinical Sciences, Medical Life Science, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan. Electronic address: skasumi@clin.medic.mie-u.ac.jp.
Kasumi
K
Shimizu
Department of Oral and Maxillofacial Surgery, Department of Clinical Sciences, Medical Life Science, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
Hiroshi
H
Morita
Department of Oral and Maxillofacial Surgery, Department of Clinical Sciences, Medical Life Science, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
Madoka
M
Inui
Cardiovascular Pulmonary Branch, NHLBI, NIH, Bethesda, MD 20892, USA.
Vincent C
VC
Manganiello
Department of Oral and Maxillofacial Surgery, Department of Clinical Sciences, Medical Life Science, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
Toshiro
T
Tagawa
Department of Oral and Maxillofacial Surgery, Department of Clinical Sciences, Medical Life Science, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan.
Naoya
N
Arai
D015124:8-Bromo Cyclic Adenosine Monophosphate / Q000494:pharmacology; D000225:Adenine / Q000031:analogs & derivatives / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D006152:Cyclic GMP / Q000031:analogs & derivatives / Q000494:pharmacology; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008545:Melanoma / Q000201:enzymology* / Q000378:metabolism / Q000473:pathology; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000378:metabolism; D020889:Rolipram / Q000494:pharmacology
D034741:RNA, Small Interfering; D015124:8-Bromo Cyclic Adenosine Monophosphate; C016276:8-bromocyclic GMP; C010192:9-(2-hydroxy-3-nonyl)adenine; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D054678:Cyclic Nucleotide Phosphodiesterases, Type 2; C517275:PDE2A protein, human; D006152:Cyclic GMP; D000225:Adenine; D020889:Rolipram
Cell growth; Cyclic AMP; Human malignant melanoma; Invasion; Phosphodiesterase 2