Abstract
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide that elicits the increase of intracellular cAMP levels and protein kinase A activity in various cell systems. Here we show that the pattern of cAMP elevation triggered by PACAP is critical for the fate of LNCaP prostate cancer cells. We demonstrate that these cells express PACAP and its type 1 receptor. A short-term stimulation with PACAP, which generates a transient cAMP rise, induces proliferation of LNCaP cells through a protein kinase A-dependent activation of the MAPK cascade. On the contrary, we observed that chronic PACAP stimulation, giving rise to a sustained cAMP accumulation, leads to proliferation arrest and neuroendocrine differentiation. Moreover, PACAP stimulates phosphory-lation and activation of the cAMP response element binding transcription factor (CREB), and MAPK activation is necessary for its full transcriptional activity, indicating a direct involvement of cAMP response element in PACAP action. These findings demonstrate that a crucial event determining the outcome of prostatic cancer cells progression is the sustained vs. transient intracellular cAMP increase.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Cell Differentiation / drug effects
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Cell Division / drug effects
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Cyclic AMP / metabolism
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Cyclic AMP Response Element-Binding Protein / metabolism
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Cyclic AMP-Dependent Protein Kinases / metabolism
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DNA / biosynthesis
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Gene Expression / physiology
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Humans
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Male
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases / metabolism
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Mitogens / pharmacology*
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Neuropeptides / genetics
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Neuropeptides / pharmacology*
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Neurosecretory Systems / cytology*
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Phosphorylation
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Pituitary Adenylate Cyclase-Activating Polypeptide
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Prostatic Neoplasms*
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Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide
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Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
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Receptors, Pituitary Hormone / genetics
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Transcription, Genetic / physiology
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Tumor Cells, Cultured / cytology
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Tumor Cells, Cultured / drug effects
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Tumor Cells, Cultured / metabolism
Substances
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ADCYAP1 protein, human
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Cyclic AMP Response Element-Binding Protein
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Mitogens
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Neuropeptides
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Pituitary Adenylate Cyclase-Activating Polypeptide
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Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide
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Receptors, Pituitary Adenylate Cyclase-Activating Polypeptide, Type I
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Receptors, Pituitary Hormone
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DNA
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Cyclic AMP
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Cyclic AMP-Dependent Protein Kinases
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Mitogen-Activated Protein Kinases