Adrenomedullin (AM) and AM receptor type 2 expression is up-regulated in prostate carcinomas (PC), and AM stimulates in vitro growth of a PC-derived cell line by enhancing proliferation and decreasing apoptosis rates
Adrenomedullin (AM) is a hypotensive peptide, that acts via the calcitonin receptor-like receptor (CRLR), whose interaction with the subtypes 2 and 3 of a family of receptor activity-modifying proteins (RAMP) gives rise to two distinct AM receptors, named AM1 and AM2 receptors. AM derives
from the post-translational proteolytic cleavage of pro(p)AM, the last step of which involves the conversion of the inactive AM to active AM by the peptidyl-glycine α-amidating monooxigenase (PAM). Compelling evidence suggests that AM, in addition to exerting its well-known regulatory
action on blood pressure and water and electrolyte balance, also possesses a growth promoting effect in several normal and neoplastic tissues, including human prostate. Conventional reverse transcription (RT)-polymerase chain reaction (PCR) demonstrated the expression of pAM, PAM, CRLR and
RAMP1-3 mRNAs in both prostate hyperplasias (PH) and carcinomas (PC), and semiquantitative PCR showed that pAM, PAM and RAMP3 mRNA expression was higher in PCs than PHs. Radioimmunoassay measured higher concentrations of immunoreactive AM in PCs than PHs. The expression of pAM, CRLR and RAMP1,2
mRNAs was also detected in the PC-derived cell lines PC-3 and DU-145, RAMP3 expression being restricted to the latter line. AM did not affect the growth rate (duplication time) of PC-3 cells, but it did significantly increase that of DU-145 cells. The growth promoting effect of AM was found
to ensue from both the rise in the proliferation rate and the lowering in the apoptosis rate of DU-145 cells. These effects of AM were counteracted by the AM receptor antagonists CGRP8-37 and AM22-52, the former antagonist, which is more selective for AM2 than AM1 receptors, being more effective
than the latter one. Both antagonists were per se able to induce a slow, but significant decrease in the basal growth rate of DU-145 cells by inhibiting proliferation and enhancing apoptosis, again CGRP8-37 being more effective than AM22-52. Taken together, our findings allow us to suggest
that: i) endogenous AM system plays an important autocrine-paracrine growth promoting action in the human prostate, being possibly involved in the development of the malignant phenotype of epithelial cells; and ii) the tumor promoting effect of AM in the human prostate is mainly mediated by
the AM2 receptor (CRLR/RAMP3) subtype.
Document Type: Research Article
Affiliations: Department of Human Anatomy and Physiology, Section of Anatomy, School of Medicine, University of Padua, I-35121 Padua, Italy
Publication date: 01 December 2004
- The International Journal of Oncology provides an international forum for the publication of the latest, cutting-edge research in the broad area of oncology and cancer treatment. The journal accepts original high quality works and reviews on all aspects of oncology research including carcinogenesis, metastasis, epidemiology, chemotherapy and viral oncology. Through fair and efficient peer review, the journal is dedicated to publishing top tier research in the field, offering authors rapid publication as well as high standards of copy-editing and production. The International Journal of Oncology is published on a monthly basis in both print and early online.
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