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      Antiproliferative Effects of GnRH Agonists: Prospects and Problems for Cancer Therapy

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          Abstract

          Gonadotropin-releasing hormone (GnRH) receptor activation has been demonstrated to inhibit cell proliferation in vitro and in vivo. These effects are dependent on the degree of receptor expression and the intracellular signaling protein milieu. The physiological and pathophysiological relevance is largely undefined, and its potential for exploitation in the treatment of specific malignancies is the subject of ongoing investigations. GnRH receptors are expressed in embryonic, juvenile and adult tissues, including brain, pituitary, gonads, accessory reproductive organs and placenta. The levels of receptor expression vary, from high in pituitary gonadotropes to low in peripheral tissues, although quantification of functional receptor protein has been determined in relatively few cell types. Roles for GnRH receptor signaling at different stages of animal development and its influence on reproductive health remain largely unexplored, except in cases of hereditary hypogonadal infertility. In addition to regulating hormone secretion, GnRH is postulated to act as a chemokine or a growth- and differentiation-inducing factor. Hence, receptor activation may influence the function of neuronal networks in the brain and the maturation of reproductive tissue epithelia. GnRH may also potentially influence the biology of cancerous cells in reproductive tissue since receptor activation may signal terminal differentiation, cell cycle arrest or apoptosis. In this context, the cell surface expression of GnRH receptor is important since it influences the intensity of intracellular signaling, and correlates with the ability to inhibit proliferation in transformed cells in vitro. Here, we review data on the effects of GnRH agonists on cell proliferation and apoptosis, and put forward hypotheses for investigation to determine whether the GnRH receptor acts as a tumor suppressor in neuroendocrine or epithelial cells.

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          Most cited references 92

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          Specificity of receptor tyrosine kinase signaling: transient versus sustained extracellular signal-regulated kinase activation.

          A number of different intracellular signaling pathways have been shown to be activated by receptor tyrosine kinases. These activation events include the phosphoinositide 3-kinase, 70 kDa S6 kinase, mitogen-activated protein kinase (MAPK), phospholipase C-gamma, and the Jak/STAT pathways. The precise role of each of these pathways in cell signaling remains to be resolved, but studies on the differentiation of mammalian PC12 cells in tissue culture and the genetics of cell fate determination in Drosophila and Caenorhabditis suggest that the extracellular signal-regulated kinase (ERK-regulated) MAPK pathway may be sufficient for these cellular responses. Experiments with PC12 cells also suggest that the duration of ERK activation is critical for cell signaling decisions.
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            Gonadotropin-releasing hormone receptors.

            GnRH and its analogs are used extensively for the treatment of hormone-dependent diseases and assisted reproductive techniques. They also have potential as novel contraceptives in men and women. A thorough delineation of the molecular mechanisms involved in ligand binding, receptor activation, and intracellular signal transduction is kernel to understanding disease processes and the development of specific interventions. Twenty-three structural variants of GnRH have been identified in protochordates and vertebrates. In many vertebrates, three GnRHs and three cognate receptors have been identified with distinct distributions and functions. In man, the hypothalamic GnRH regulates gonadotropin secretion through the pituitary GnRH type I receptor via activation of G(q). In-depth studies have identified amino acid residues in both the ligand and receptor involved in binding, receptor activation, and translation into intracellular signal transduction. Although the predominant coupling of the type I GnRH receptor in the gonadotrope is through productive G(q) stimulation, signal transduction can occur via other G proteins and potentially by G protein-independent means. The eventual selection of intracellular signaling may be specifically directed by variations in ligand structure. A second form of GnRH, GnRH II, conserved in all higher vertebrates, including man, is present in extrahypothalamic brain and many reproductive tissues. Its cognate receptor has been cloned from various vertebrate species, including New and Old World primates. The human gene homolog of this receptor, however, has a frame-shift and stop codon, and it appears that GnRH II signaling occurs through the type I GnRH receptor. There has been considerable plasticity in the use of different GnRHs, receptors, and signaling pathways for diverse functions. Delineation of the structural elements in GnRH and the receptor, which facilitate differential signaling, will contribute to the development of novel interventive GnRH analogs.
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              Isolation and functional characterization of murine prostate stem cells.

              The ability to isolate prostate stem cells is essential to explore their role in prostate development and disease. In vitro prostate colony- and sphere-forming assays were used to quantitatively measure murine prostate stem/progenitor cell enrichment and self-renewal. Cell surface markers were screened for their ability to positively or negatively enrich for cells with enhanced growth potential in these assays. Immunohistochemical and FACS analyses demonstrate that specific cell surface markers can be used to discriminate prostate stromal (CD34(+)), luminal epithelial (CD24(+)CD49f(-)), basal epithelial (CD24(+)CD49f(+)), hematopoietic (CD45(+), Ter119(+)), and endothelial (CD31(+)) lineages. Sorting for cells with a CD45(-)CD31(-)Ter119(-)Sca-1(+)CD49f(+) antigenic profile results in a 60-fold enrichment for colony- and sphere-forming cells. These cells can self-renew and expand to form spheres for many generations and can differentiate to produce prostatic tubule structures containing both basal and luminal cells in vivo. These cells also localize to the basal cell layer within the region of the gland that is proximal to the urethra, which has been identified as the prostate stem cell niche. Prostate stem cells can be isolated to a purity of up to 1 in 35 by using this antigenic profile. The remarkable similarity in cell surface profile between prostate and mammary gland stem cells suggests these markers may be conserved among epithelial stem cell populations.
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                Author and article information

                Journal
                NEN
                Neuroendocrinology
                10.1159/issn.0028-3835
                Neuroendocrinology
                S. Karger AG
                0028-3835
                1423-0194
                2008
                August 2008
                29 February 2008
                : 88
                : 2
                : 67-79
                Affiliations
                Medical Research Council Human Reproductive Sciences Unit, Centre for Reproductive Biology, The Queen’s Medical Research Institute, Edinburgh, UK
                Article
                119093 Neuroendocrinology 2008;88:67–79
                10.1159/000119093
                18309229
                © 2008 S. Karger AG, Basel

                Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.

                Page count
                Figures: 5, Tables: 1, References: 127, Pages: 13
                Categories
                At the Cutting Edge

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