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Expression of Adrenomedullin and Peptide Amidation Activity in Human Prostate Cancer and in Human Prostate Cancer Cell Lines¹

Laboratoire de Cancérologie Expérimentale-EA 2671/Laboratoire de Transfert, Assistance Publique-Hopitaux de Marseille (AP-HM), 13916 Marseille Cedex 20 [P. R., F. B., X. M., P-M. M., L. O.]; Interactions Cellulaires Neuroendocriniennes Unité Mixte de Recherche 6544 Centre National de Recherche Scientifique, Institute Federatif de Recherche Jean Roche, Faculté de Médecine Nord 13916 Marseille Cedex 20 [A. J. Z.]; Service de Radiothérapie, Centre Hospitalier Universitaire Timone, Marseille 13005 AP-HM [X. M.]; and Service d’Urologie, Hopital Salvator AP-HM Marseille 13009 [E. L.], France

After therapeutic hormone deprivation, prostate cancer (CaP) cells often develop androgen-independent growth through not-well-defined mechanisms. The presence of neuroendocrine (NE) cells is often greater in prostate carcinoma than in normal prostate, and the frequency of NE cells correlates with tumor malignancy, loss of androgen sensitivity, increase of autocrine-paracrine activity, and poor prognosis. In some CaPs, neuropeptides have been previously implicated as growth factors. Peptidylglycine -amidating monooxygenase (PAM) is the enzyme producing -amidated bioactive peptides from their inactive glycine-extended precursors. In the present work, we demonstrate that androgen-independent PC-3 and DU145 cell lines, derived from human CaP, express PAM in vitro and in xenografts implanted in athymic nude mice, indicating that they are able to produce -amidated peptides. Contrarily, barely detectable levels of PAM were found in the androgen-sensitive LNCaP cell line. We also show that whereas PC-3 and DU145 cells produce and secrete adrenomedullin (AM), a multifunctional amidated peptide, no expression was found in LNCaP cells. We further demonstrate that AM acts as a growth factor for DU145 cells, which suggests the existence of an autocrine loop mechanism that could potentially drive neoplastic growth. PAM mRNA levels were found to be 3-fold higher in prostate adenocarcinomas compared with that of human benign prostate hyperplasia (BPH) as demonstrated by real-time quantitative reverse transcription-PCR. The analysis of AM message expression in BPH and CaP (Gleason’s score, 6–9) shows a clear distinction between benign and CaP. The expression was detected only in adenocarcinomas tissues with a marked increase in samples with a high Gleason’s score. Immunocytochemically, AM was localized in the carcinomatous epithelial compartment. NE phenotype, assessed after the immunocytochemical localization of neuron-specific enolase (NSE), was found in both the epithelial and the stromal compartments of cancers; in BPH, only some spare basal cells were NSE-labeled. Cancer progression could be accelerated by peptides secreted by a population of cells capable of inducing androgen-independent tumoral growth via autocrine-paracrine mechanisms.

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