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REVIEW |
1 Centre for Medical Education, University of Bristol, 39–41 St Michael's Hill, Bristol BS2 8DZ, UK
2 Department of Obstetrics and Gynecology, Uniformed Services University of the Health Sciences, 4301 Jones Bridge Road, Bethesda, Maryland 20814, USA
Correspondence should be addressed to T J Wu; Email: twu{at}usuhs.mil
K Cleverly is now at Newham University Hospital, Glen Road, London E13 8BL, UK 
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Abstract |
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Introduction |
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Many laboratories including those of Drs Samuel McCann, Andrew Schally and Roger Guillemin were involved in the characterisation of this neurohormone. The studies from these laboratories led to the elucidation of its structure and functions (Gore 2002, Limonta et al. 2003).
First, discovered and characterised in mammals, the hypophysiotropic form of the peptide (pGlu-His-Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) is part of a much larger family of decapeptides. Over 20 forms of naturally occurring LHRHs have been described in a variety of mammalian and non-mammalian species (Millar 2005). Their nomenclature is originally based upon the species from which they were first described. Furthermore, within each species, there may be one or more LHRH forms where some of these peptide structures are common across species. In this particular review that focuses on mammalian biology and clinical literature, the mammalian LHRH is designated LHRH-I as recommended by others (Wray 2002, Schneider et al. 2006).
In the adult, LHRH-I neurons are widely distributed along the rostrocaudal axis in the basal forebrain region around the preoptic area. The brain and pituitary localisation of LHRH has been extensively reviewed elsewhere (Wu et al. 1997, Gore 2002). Studies conducted in a variety of species have identified LHRH-I production along with its binding site and cognate receptor, the LHRH-RI, in non-hypothalamic tissue (Leung et al. 2003, Ramakrishnappa et al. 2005, Walters et al. 2008), suggesting a role for this neuroendocrine hormone beyond the pituitary. The wide and varied distribution of LHRH-I underscores the complexity of its function. Much of its biology remains to be elucidated.
Following its release, LHRH is degraded by intracellular peptidases. It has been suggested that the zinc metalloendopeptidase EC 3.4.24.15 [EC] (also known as EP24.15 or thimet oligopeptidase) is the main mediator of this process in both the brain and periphery. Other intracellular peptidases, such as the angiotensin-converting enzyme (ACE), in the process of degradation produce peptide fragments with biological activity. When degrading LHRH, EP24.15 produces the pentapeptide fragment LHRH-(1–5). Work is emerging and suggesting that this peptide fragment has biological activity separate from that of its parent peptide. Biologically, its effects may be different to or even antagonise those of its parent peptide.
In this review, we present the evidence that EP24.15 is the main enzyme of LHRH metabolism. Following this, we look at the metabolism of other neuropeptides where an active peptide fragments is formed during degradation and use this as a platform to postulate that EP24.15 may also produce an active peptide fragment in the process of breaking down LHRH. Evidence is accumulating for clinically important direct peripheral effects of LHRH and LHRH agonists are being widely used for a number of clinical applications. In light of this it is interesting to note that the LHRH agonists in current use are not substrates for EP24.15. We close this review by the role EP24.15 may have in regulation of the complex LHRH system.
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LHRH-I is processed by a metalloendopeptidase |
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MSH and β-endorphin. The cascade of intracellular processes within nerve cells that results in the formation of active neuropeptides not only regulates the quantity of neuropeptide produced but also its bioactivity. The end result of cleavage of a large precursor molecule is a set of neuropeptides that may have similar, opposite, different or more selective properties. Following secretion into the extracellular area, these neuropeptides may be further processed. The peptide fragments formed following their degradation may provide an additional layer of regulation, demonstrating different effects to their parent peptides.
Zinc metalloendopeptidase EP24.15 has a crucial role in the processing of LHRH-I
The 75 kDa EP24.15 is the main enzyme in the metabolism of LHRH-I. This endopeptidase was first identified in the soluble fraction of rat brain homogenates (Orlowski et al. 1983) and is widely distributed in a variety of cell and tissue types (Müller et al. 1997, Tullai et al. 2000, Grundker et al. 2001, Tiong et al. 2004, Ramakrishnappa et al. 2005). Enzymatic activity is dependent upon phosphorylation by protein kinase A (PKA; Tullai et al. 2000) and as a thermolysin like metalloendopeptidase, the enzyme is zinc dependent (Dong et al. 1993). Substrate specificity is dependent upon peptide size (<17 amino acids), with no clear preference for amino acid sequence (Ray et al. 2004). However, a preference for a hydrophobic amino acid residue in the P1 and P2 positions along with a bulky hydrophobic residue in the P3' position has been demonstrated (Swanson et al. 2004).
The spatial and temporal location of EP24.15 demonstrates its important role in the processing of LHRH-I. Confocal microscopy has demonstrated EP24.15 in the external layer of the median eminence and preoptic area, where it can be seen co-localised with LHRH-I axon terminals (Wu et al. 1997). For a processing enzyme to play an important physiological role in neuropeptide processing and regulation it must be localised extra-cellularly (Kim et al. 2003). Many enzymes involved in neuropeptide degradation are either anchored to the extracellular membrane or free in the extracellular fluid. EP24.15, however, is predominantly found in the cytoplasm and is secreted into the extracellular space via poorly understood mechanisms. EP24.15 does not contain a membrane-anchoring motif yet it has been localised to the extracellular surface of the plasma membrane (Crack et al. 1999) as well as the exofacial leaflet of the lipid raft microenvironment (Jeske et al. 2004). Peripherally, EP24.15 is found in tissues under the control of LHRH-I regulation, the highest known levels of being found in the testis. Here, the enzyme's activity levels rise in a linear fashion with age and is thought to have a role in spermatogenesis (Pierotti et al. 1991, Pineau et al. 1999). Levels in the rat ovary are similar to those seen in the brain and increase sharply during puberty (before falling away in adulthood; Pierotti et al. 1991). In addition, activity levels fluctuate during the proestrous period in the rat; with peak activity coinciding with the ascending phase of the LH surge (Wu et al. 1997). A regulatory role of circulating steroid hormones in the activity levels of this enzyme has therefore been suggested. Physiological data adds further weight to the idea that EP24.15 is the in vivo processing enzyme of LHRH-I. I.c.v. administration of a specific inhibitor of EP24.15 leads to an eightfold increase in the half-life of LHRH-I (Lasdun et al. 1989) and its peripheral administration augments the LHRH-I dependent surge of LH in the rat (Wu et al. 1997).
Activity of EP24.15 is regulated by phosphorylation of serine residue 644 by PKA. Phosphorylation of this conserved site reduces enzyme affinity for binding LHRH-I. However, once LHRH-I is bound the phosphorylated enzyme can rapidly turn over large quantities of substrate. The ability of phosphorylated EP24.15 to handle large quantities of substrate before saturating adds further evidence for the important regulatory role this enzyme has in the pulsatile LHRH-I waveform (Tullai et al. 2000). Therefore, while other enzymes may also play a role in LHRH-I metabolism, it is proposed that EP24.15 is the prime mediator of LHRH-I degradation in both the brain and periphery. Consequently, regulation of this enzymes activity may provide an additional mechanism of control of reproductive tissue.
Processed peptides have biological activity
EP24.15 is not the only intracellular peptidase thought to have activities beyond degradation. Other metallopeptidases such as the ACE are known to, in the process of cleavage, activate peptides allowing them to profoundly affect physiology. Some examples to support the concept that active neuropeptides are converted by peptidases to fragments that are biologically active are shown in Table 1.
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LHRH-I is metabolised by a two-step process
The mechanism of metabolism of LHRH suggests that EP24.15 converts rather than degrades the peptide. EP24.15 cleaves LHRH at the Tyr5-Gly6 bond producing its major degradation product, LHRH-(1–5). Interestingly, kinetic analysis has shown that LHRH is a poor substrate for EP24.15. However, LHRH-(1–9), a peptide fragment produced by the action of prolyl endopeptidase on LHRH, has a much greater Km (Lew et al. 1994). It is therefore suggested that the conversion of LHRH to its major product LHRH-(1–5) occurs via a two-step mechanism. Firstly, LHRH-(1–9) is generated by prolyl endopeptidase. Conversion by EP24.15 to LHRH-(1–5) then occurs. It is suggested that the carboxy terminal glycine that is removed in the first metabolic step significantly hinders the ability of EP24.15 to cleave LHRH-I.
The two-step mechanism of LHRH metabolism highlights the substrate specificity of EP24.15 suggesting it has a role above simple inactivation. In addition, it has been suggested that a free carboxyl terminus may be required for binding to neutral endopeptidases such as EP24.15 (Orlowski et al. 1983), a similar mechanism seen with the degeneration of LHRH-I and bradykinin by endo-oligopeptidase A. This enzyme will cleave the Tyr-Gly bond only after the removal of glycine from the COOH terminus (De Camargo et al. 1982). Substituting an amide for the carboxy group reduced hydrolysis, as carboxypeptidases do not cleave alpha amidated peptides efficiently. Therefore, it can be postulated that the carboxy terminal amidation seen in the metabolism of LHRH-I may protect this neuropeptide from non-specific degredation (Lew et al. 1994).
EP24.15 is an activating enzyme
EP24.15 is known to degrade a number of important bioactive peptides in addition to LHRH-I, for example bradykinin and neurotensin. Classically, EP24.15, as an endopeptidase is thought to degrade neuropeptides terminating their physiological function. It was initially classified as a metabolising enzyme that terminated function through hydrolysis, rendering its substrate unable to bind to the cognate receptor (Orlowski et al. 1989, Dahms & Mentlein 1992, Montiel et al. 1997). Current thinking is that EP24.15 has a number of alternative physiological functions (Kim et al. 2003). Firstly, it can transform an inert precursor neuropeptide into an active peptide. This is seen in the activation of neoendorphin (to Leu-enkephalin) by EP24.15 (Acker et al. 1987). Secondly, it acts as a convertase, changing one bioactive peptide into a different peptide that either binds to a different receptor or binds to the same receptor but conveys different downstream messages. For example, EP24.15 can convert the decapeptide LHRH-I to the pentapeptide LHRH-(1–5). This fragment does not bind to LHRH-RI instead it has antagonistic properties at the N-methyl-D-aspartic acid (NMDA) receptor (Bourguignon et al. 1994). Finally, EP24.15 has a biomodulating action, forming a peptide product that opposes the action of its parent peptide. This is seen with the conversion of angiotensin I to the hypotensive fragment angiotensin-(1–7) by EP24.15 rather than to the hypertensive fragment angiotensin-(1–8) (angiotensin II) by ACE (Chappell et al. 2004).
The many roles of EP24.15 in the metabolism of neuropeptides suggest that this enzyme has a role in cell regulation. Using an inactive EP24.15 ‘substrate capture’ assay in rat brain tissue Cunha et al. (2008) identified nine novel peptides that bound to the enzyme. They subsequently demonstrated that three of these peptides when introduced into CHO-S and HEK293 cells were able to alter GPCR signal transduction. The modulation of GPCR activity was shown to involve the proteins interacting with EP24.15. Adding these peptides intracellularly or overexpression of the enzyme modulated cell functioning suggesting physiological consequences of this signalling effect. This data suggest that EP24.15 and the peptides this enzyme may cleave are regulators of GPCR signal transduction.
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Possible role for a metabolite of LHRH-I, LHRH-(1–5) |
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LHRH-(1–5) has also been shown to affect sexual behaviour (Wu et al. 2006). Specifically, i.c.v. administration of LHRH-(1–5) facilitated the lordosis response in ovariectomised female rats. It is interesting to also note that LHRH-(1–5) has proliferative effects in the Ishikawa endometrial cell line (Walters et al. 2007) and a number of ovarian surface epithelial cell lines such as those previously shown to be responsive to direct LHRH-I effect (K Walters & T J Wu, unpublished observations). The ability of LHRH-(1–5) to stimulate proliferation appears to be linked to suppression of caspase-3/7 and ERK-1/2 expression (Walters et al. 2007). It is possible that EP24.15 expression is altered in cancer, resulting in an increase in production of LHRH-(1–5). This in turn may contribute to greater growth and the diminishing role of LHRH-I in regulating the extracellular matrix and activating the apoptosis pathway.
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LHRH-I locally regulates healthy reproductive and non-reproductive tissue |
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Historically, LHRH-I is a regulator of reproduction
Throughout evolution, the LHRH-I system has been shown to provide a link between the nervous and reproductive systems (Tsai 2006). It has been suggested that the LHRH-I neurons seen in non-chordate invertebrates, who lack a hypothalamic–pituitary–gonadal axis (HPG axis), secreted LHRH-I directly into the blood stream from where it had a direct action on the gonads (Powell et al. 1996, Rastogi et al. 2002). LHRH-I may have developed as an early neuropeptide with a generalised neurotransmitter or neuromodulatory action in simple unicellular and multicellular organisms. As these organisms evolved, LHRH-I could have been recruited by the nerve cells and used to activate reproduction. First by direct action on the gonads and later through the regulation of the pituitary gland (Millar 2005). Early elaboration of LHRH-I function may have involved sensitising the neuroepithelium to pheremones as is seen in bony fish. Therefore, it is suggested that whilst LHRH-I was primarily recruited to regulate reproduction via the HPG axis it may maintain a regulatory role in peripheral reproductive and non-reproductive tissues.
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LHRH and its receptor are present in peripheral reproductive tissues |
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Evidence for the presence of LHRH-I gene transcripts, binding sites and mRNA have been demonstrated in the rat ovary. Although data from human ovaries has been more variable, LHRH-I and LHRH-RI mRNA has been demonstrated using RT-PCR in both the fresh and cultured granulose luteal cells of women undergoing IVF (Peng et al. 1994, Minaretzis et al. 1995). More specifically in situ autoradiography has shown high affinity binding of LHRH-I to the granulose cells of the dominant follicle with low affinity binding sites seen in corpus luteum homogenates (Bramley et al. 1985, Latouche et al. 1989).
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LHRH has direct antiproliferative effects in reproductive tissues |
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i protein, one explanation of this differing effect (Wu et al. 2009). The emerging evidence regarding LHRH-(1–5) suggests that this active peptide fragment has a proliferative effect on tumour cells. The downstream signalling pathway of this effect is as yet unknown but one could speculate as to a balanced regulatory system with proliferation being influenced by varying levels of LHRH and LHRH-(1–5). The enzyme EP24.15 and regulation of its activity could therefore have a role in cellular proliferation of reproductive tissues. |
LHRH agonists are not degraded by EP24.15 |
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The LHRH system is active in peripheral tissue |
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Prostate tissue
LHRH-I analogues have been used in the treatment of prostate cancer since the early 1980's (Labrie et al. 1982, Plosker & Brogden 1994). In the androgen-dependent phase of the disease their major effect is via suppression of the HPG axis, with an early worsening of symptoms (e.g. pain from bone metastasis) frequently observed prior to agonist induced suppression of pituitary function, an effect that can be reversed with use of anti-androgens (Sogani & Fair 1987). Evidence for an additional direct effect comes from in vitro experiments where LHRH-I agonists exert an inhibitory effect on the androgen induced proliferation of prostate cancer cells in a dose-dependent manner (Limonta et al. 1992, 1999). When the cell line ALVA-31 was xenografted into surgically castrated male mice, treatment with leuprolide inhibited its growth (Loop et al. 1995). These results suggest an alternative mechanism of LHRH-I action independent of the suppressive effect on the HPG axis. Prostate cancer tends to progress to a stage of androgen independence. It has been suggested that in this phase LHRH-I agonists may have a direct anti-tumour effect. In androgen insensitive prostate cancer cells, treatment with LHRH-I results in blockade of the fibroblast growth factor induced proliferation and invasion only in tumour cells with very high expression levels of LHRH-RI (Gnanapragasam et al. 2005). LHRH-I agonist therapy was then shown to improve survival only in patients with a high expression of LHRH-IR, an effect not seen when this subset of patients underwent surgical castration.
Mammary tissue
LHRH-I agonists are used as adjuvant therapy in oestrogen receptor (ER) or progesterone receptor positive pre-menopausal breast cancer as well as in salvage therapy for advanced disease. Interestingly, the combined effect of ER blockade (with tamoxifen) and LHRH-I agonist treatment was shown to be superior to either individual treatment in early breast cancer (Klijn et al. 2001). Whether this is due to suppression of the tamoxifen induced stimulation of pituitary function or due to a direct effect of the LHRH-I analogue on breast cancer cells remains to be determined. Evidence for the latter explanation comes from in vitro studies on the oestrogen insensitive breast cancer cell line, MDA-MB 231, in which LHRH-I was anti-proliferative. This effect remained when the cells were xenografted into mice (Vincze et al. 1991). The absence of active ERs on this cell line suggests an effect of LHRH-I above suppression of circulating levels of sex steroids.
LHRH-I produced peripherally acts via its cognate receptor on a number of peripheral reproductive tissues. This direct local effect on both healthy and diseased tissue has a number of clinical implications. Further understanding of the regulation of this system is needed before the full scope of their potential clinical use can be described. Specifically, there is the possibility of an additional level of regulation, via the downstream processing of this peripherally produced LHRH by EP24.15.
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Summary |
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It is known that pro-hormone precursors are cleaved to form variety of neuropeptides often with different actions. In this review an additional layer of regulation is proposed; that is that following secretion neuropeptides are further cleaved to form additional active peptide fragments. LHRH-I is processed by the endopeptidase, EP24.15, to form LHRH (1–5), a fragment that has contrasting biological activity to its parent peptide. Levels of EP24.15 may be used to balance the action of the different peptides, both centrally and peripherally. Disruption of this regulation may lead to disordered cellular proliferation with consequent pathology.
The LHRH-I agonists in current clinical use are not substrates for EP24.15. Their use may shift the balance of LHRH-I activity in peripheral tissues towards anti-proliferation. This is a potential additional explanation for the peripheral actions of these drugs. In addition further description of the action and receptor of LHRH (1–5) may present a possible therapeutic target for antiproliferatives.
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Declaration of interest |
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Funding |
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Acknowledgements |
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Received March 31, 2009
First decision May 1, 2009
Revised manuscript received August 25, 2009
Accepted September 15, 2009
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Abstract
Introduction