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Dual Effect of Pituitary Adenylate Cyclase Activating Polypeptide on Prostate Tumor LNCaP Cells: Short- and Long-Term Exposure Affect Proliferation and Neuroendocrine Differentiation

Department of Public Health and Cellular Biology, Unit of Histology (D.F., A.P., G.S.), and Department of Internal Medicine, Unit of Endocrinology (C.Ma., C.Mo.), University of Rome "Tor Vergata," 00133 Rome, Italy

Address all correspondence and requests for reprints to: Costanzo Moretti, M.D., Department of Internal Medicine, Chair of Endocrinology, Faculty of Medicine, University of Rome "TorVergata," Via di TorVergata 135, 00133 Rome, Italy. E-mail: moretti{at}med.uniroma2.it.

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.

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