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Microarray and Suppression Subtractive Hybridization Analyses of Gene Expression in Pheochromocytoma Cells Reveal Pleiotropic Effects of Pituitary Adenylate Cyclase-Activating Polypeptide on Cell Proliferation, Survival, and Adhesion

Institut Fédératif de Recherches Multidisciplinaires sur les Peptides (IFRMP 23), Laboratory of Cellular and Molecular Neuroendocrinology (L.G., H.G., D.A., L.Y., H.V., Y.A.), Institut National de la Santé et de la Recherche Médicale (INSERM) U413, University of Rouen, 76821 Mont-Saint-Aignan, France; Cancer Genetics Branch (A.G.E.), National Human Genome Research Institute, National Institutes of Health, Bethesda, Maryland 20892; IFRMP 23, INSERM U519, Faculty of Medicine and Pharmacy (C.C., J.-P.S.), 76183 Rouen, France; Section on Molecular Neuroscience, Laboratory of Cellular and Molecular Regulation (L.E.E.), National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892; and Institut National de la Recherche Scientifique-Institut Armand Frappier (A.F.), University of Quebec, Pointe Claire, Montréal, Canada H9R 1G6

Address all correspondence and requests for reprints to: Hubert Vaudry, European Institute for Peptide Research (IFRMP 23), Laboratory of Cellular and Molecular Neuroendocrinology, Institut National de la Santé et de la Recherche Médicale (INSERM) U413, UA Centre National de la Recherche Scientifique, University of Rouen, 76821 Mont-Saint-Aignan, France. E-mail: hubert.vaudry{at}univ-rouen.fr.

Pituitary adenylate cyclase-activating polypeptide (PACAP) exerts trophic effects on several neuronal, neuroendocrine, and endocrine cells. To gain insight into the pattern of the transcriptional modifications induced by PACAP during cell differentiation, we studied the effects of this neuropeptide on rat pheochromocytoma PC12 cells. We first analyzed the transcriptome of PC12 cells in comparison to that of terminally differentiated rat adrenomedullary chromaffin cells, using a high-density microarray, to identify genes associated with the proliferative phenotype that are possible targets of PACAP during differentiation of sympathoadrenal normal and tumoral cells. We then studied global gene expression in PC12 cells after 48 h of exposure to PACAP, using both cDNA microarray and suppression subtractive hybridization technologies. These complementary approaches resulted in the identification of 75 up-regulated and 70 down-regulated genes in PACAP-treated PC12 cells. Among the genes whose expression is modified in differentiated cells, a vast majority are involved in cell proliferation, survival, and adhesion/motility. Expression changes of most of these genes have been associated with progression of several neoplasms. A kinetic study of the effects of PACAP on some of the identified genes showed that the neuropeptide likely exerts early as well as late actions to achieve the gene expression program necessary for cell differentiation. In conclusion, the results of the present study underscore the pleiotropic role of PACAP in cell differentiation and provide important information on novel targets that could mediate the effects of this neuropeptide in normal and tumoral neuroendocrine cells.

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