Báo cáo khoa học: Gonadotropin-releasing hormone: GnRH receptor signaling in extrapituitary tissues

M I N I R E V I E W

Gonadotropin-releasing hormone: GnRH receptor signaling in extrapituitary tissues Lydia W. T. Cheung and Alice S. T. Wong

School of Biological Sciences, University of Hong Kong, China

Keywords cross-talk; extrapituitary; GnRH; GnRH receptor; MAPK; metastasis; pituitary; receptor tyrosine kinase; signaling; tumor

Correspondence A. S. T. Wong, School of Biological Sciences, University of Hong Kong, 4S-14 Kadoorie Biological Sciences Building, Pokfulam Road, Hong Kong, China Fax: +852 2559 9114 Tel: +852 2299 0865 E-mail: awong1@hku.hk

(Received 14 April 2008, revised 28 May 2008, accepted 11 June 2008)

doi:10.1111/j.1742-4658.2008.06677.x

Gonadotropin-releasing hormone (GnRH) has historically been known as in the past few years, a pituitary hormone; however, interest has been raised in locally produced, extrapituitary GnRH. GnRH receptor (GnRHR) was found to be expressed in normal human reproductive tissues (e.g. breast, endometrium, ovary, and prostate) and tumors derived from these tissues. Numerous studies have provided evidence for a role of GnRH in cell proliferation. More recently, we and others have reported a novel role for GnRH in other aspects of tumor progression, such as metastasis and angiogenesis. The multiple actions of GnRH could be linked to the divergence of signaling pathways that are activated by GnRHR. Recent observations also demonstrate cross-talk between GnRHR and growth fac- the classical Gaq–11-phospholipase C signal tor receptors. Intriguingly, transduction pathway, known to function in pituitary gonadotropes, is not involved in GnRH actions at nonpituitary targets. Herein, we review the key ﬁndings on the role of GnRH in the control of tumor growth, progres- sion, and dissemination. The emerging role of GnRHR in actin cytoskele- ton remodeling (small Rho GTPases), expression and ⁄ or activity of adhesion molecules (integrins), proteolytic enzymes (matrix metalloprotein- ases) and angiogenic factors is explored. The signal transduction mecha- nisms of GnRHR in mediating these activities is described. Finally, we discuss how a common GnRHR may mediate different, even opposite, responses to GnRH in the same tissue ⁄ cell type and whether an additional receptor(s) for GnRH exists.

Introduction

to GnRH-I, GnRH-II

in contrast

The hypothalamic gonadotropin-releasing hormone (GnRH) is a decapeptide that plays a critical role in the regulation of reproduction. GnRH-I (pGlu-His- Trp-Ser-Tyr-Gly-Leu-Arg-Pro-Gly-NH2) the ﬁrst GnRH isoform discovered in mammalian brain. Its to stimulate pituitary secretion of major

role is

gonadotropins, luteinizing hormone and follicle-stimu- lating hormone, which in turn stimulate the gonads for steroid production. Subsequently, a second iso- form of GnRH (His5, Trp7, Tyr8) (GnRH-II) has been isolated from chicken brain. It is also highly conserved among vertebrates, including mammals [1]. However, is expressed at signiﬁcantly higher levels outside the

Abbreviations EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ERK, extracellular signal-related kinase; FAK, focal adhesion kinase; FGF, ﬁbroblast growth factor; GnRH, gonadotropin-releasing hormone; GnRHR, gonadotropin-releasing hormone receptor; JNK, Jun N-terminal kinase; MAPK, mitogen-activated protein kinase; MMP, matrix metalloproteinase; NF-jB, nuclear factor kappa B; PI3K, phosphatidylinositol 3-kinase; PKC, protein kinase C; Pyk2, proline-rich tyrosine kinase 2; RTK, receptor tyrosine kinase; uPA, urokinase-type plasminogen activator; VEGF, vascular endothelial growth factor.

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its

their tissue of origin, ovarian surface epithelium [9,10]. Interestingly, levels of GnRHR seem to be associated with cancer grading and have been reported to be elevated in advanced stage (stages III and IV) as compared to early stage (stages I and II) ovarian carcinomas [11]. Our recent ﬁndings that GnRH can promote the motility and invasiveness of ovarian can- cer cells further corroborate the view that GnRH may play a crucial role in tumor progression ⁄ metastasis [12,13], and these ﬁndings will be discussed in a later section.

specimens

in the kidney, brain and is particularly abundant bone marrow, and prostate [2]. This leads to the speculation that GnRH-II may have distinct physio- logical functions from those of GnRH-I. In line with this is the observation that although GnRH-II can stimulate gonadotropin secretion, efﬁciency is much lower than that of GnRH-I (only about 2% of that of GnRH-I) [3]. This suggests that the primary role of GnRH-II is not in the regulation of gonado- tropin secretion. Instead, this peptide has been shown to act as a neuromodulator [4]. The exact actions of GnRH-II in peripheral tissues are not entirely under- stood, but this is certainly an important topic for investigation which may offer an opportunity to eluci- date the undisclosed complexity of GnRH.

studied thus

Using [125I][d-Trp6]GnRH, speciﬁc receptor binding has been detected in membranes from 24 of 31 (77%) endometrial carcinomas and from three of 13 (23.1%) nonmalignant human endometrial [14]. GnRHR mRNA has been clearly detected in surgical endometrial carcinoma specimens and endometrial carcinoma cell lines [15,16]. As with normal myome- trium, most benign neoplasms far, including uterine leiomyoma, also possess GnRHR [17].

receptor

layers

cell

In this minireview, we will focus on recent progress in understanding the roles of GnRH-I and GnRH-II in particular its emerging in extrapituitary tissues, role in tumor growth, invasion, and metastasis. We will also describe the molecular mechanisms underlying these effects, focusing on the roles of proteolysis, adhesion, and signaling, as well as our still-emerging cross-talk with other understanding of pathways. Finally, we will discuss two important outstanding questions in the ﬁeld regarding what might distinguish the different responses to the same ligand (GnRH) and whether an additional receptor(s) for GnRH exists in humans.

Early studies showed that the human placenta con- tains speciﬁc binding sites for GnRH that interact with GnRH agonists and antagonists [18]. Later on, GnRHR was localized to the cytotrophoblast and [19,20]. Temporal syncytiotrophoblast expression of GnRHR in the placental cells at different weeks of gestation has been observed, in parallel with the time-course of chorionic gonadotropin secretion during pregnancy [21], suggesting that the expression of the receptor is a function of pregnancy stage.

Localization of GnRH receptor (GnRHR) in peripheral reproductive tissues

lines [5]. Soon after this, a functional

The presence of GnRHR has been demonstrated in numerous human breast cancer cell lines and tumor biopsy specimens [22–24]. GnRHR was immunolocal- ized in the cytoplasm in 37 of 58 (64%) invasive ductal carcinoma cases [23]. The expression of GnRHR in normal human breast tissue is still controversial, but the sample size may have been too small to allow any deﬁnite conclusion [22,25].

The initial interest in extrapituitary GnRHR stemmed primarily from observations in the 1980s that GnRH analogs can inhibit the growth of nonpituitary tumor cell type I GnRHR was demonstrated in a variety of normal human reproductive tissues (e.g. breast, endometrium, ovary, and prostate) and tumors derived from these tissues.

GnRHR is also present in prostate cancer cells, as shown by radioligand-binding studies, PCR, and western blotting analysis [26,27]. GnRHR immunore- activity is localized to the luminal and basal epithelial cells in benign and malignant prostate tissues. In this study, the relative GnRHR mRNA levels showed a wide range of individual differences that were unrelated to the histological grades of the 16 cases [27]. There does, however, appear to be signiﬁcantly higher expression of GnRHR in hormone-refractory prostate carcinoma than in other types of prostate tumor (n = 80) [28].

In the ovary, GnRHR mRNAs are expressed in granulosa-luteal cells, and increased expression of GnRHR correlates with follicular growth and develop- ment [6]. GnRHR binding has been demonstrated in luteinized granulosa cells, late follicles and developing corpora lutea, but not in primordial, early antral and preovulatory follicles [7,8]. This stage-speciﬁc expres- sion of GnRHR in the human granulosa and luteal cells suggests a role for GnRH in the regulation of ovarian physiology, particularly ovulation, follicular atresia and luteolysis. The presence of GnRHR protein and mRNA has also been demonstrated in human ovarian tumor specimens, ovarian cancer cell lines and

Although these extrapituitary GnRHRs share the same cDNA nucleotide sequence and encode tran- scripts and proteins of the same size as the pituitary

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GnRH-II has antiproliferative effects on ovarian cancer cells [41–43]. Although it has been suggested that this effect of GnRH-II is mediated through the type I GnRHR [43], there are other ﬁndings implicating a type I GnRHR-independent action [41,42].

It is interesting to note that although both GnRH-I agonists and antagonists exert antiproliferative effects, the effects of GnRH-I antagonists are stronger than those of the agonists [44]. This difference has also been seen in an in vivo model, which demonstrates a signiﬁ- cant inhibition of tumor growth by GnRH-I antago- nists but not GnRH-I agonists [45]. The advantage of GnRH antagonists over the agonistic peptides is prob- ably due to the fact that they inhibit the secretion of gonadotropins and reduce sex steroid levels immedi- ately after application, thus achieving rapid therapeutic effects, whereas repeated exposure to agonistic agents is required to induce functional desensitization of the gonadotropes [46].

GnRHR [20,26,29], they also differ in several ways. First, cell surface receptor expression in extrapituitary sites is low as compared to that of the pituitary [15,27]. This may underlie the greater effect of the GnRHR ligands on the gonadotropes. Second, there are at least two classes of GnRHR: one has high afﬁn- ity [with nanomolar dissociation constants (Kd)] for GnRH, and one has low afﬁnity (with micromolar Kd values) for GnRH. The high-afﬁnity GnRH-binding sites are commonly regarded as being the same as the GnRHR of the pituitary gland. Whereas in most of the reported cases, both the low-afﬁnity and high-afﬁn- ity GnRHR have been found in extrapituitary tissues [30–33], in some cases, only low-afﬁnity GnRHR could be detected [10,18,34], and in others, e.g. in endome- trial cancers and nonmalignant endometrial specimens, only the high-afﬁnity GnRHR has been demonstrated [14]. The exact role of each of these receptors and the implications of differential levels of expression remain to be elucidated.

Functions of GnRH-I and GnRH-II in cancers

Tumor growth

Treatment of human endometrial cancer cells (cell line Ishikawa) with the GnRH-I antagonist SB-75 results in growth inhibition, mainly due to the Fas ⁄ Fas ligand-mediated apoptotic pathway, whereas GnRH-I agonists have no effect on the same cell line [15,47,48]. Another endometrial carcinoma cell line, HEC-1A, also exhibits differential responses to different GnRH agon- ists and antagonists [15,30,36,48]. GnRH-II has been shown to have antiproliferative effects on endometrial carcinoma cells [41]. The effects of GnRH-I are abrogated after type I GnRHR knockout [36], whereas those of the GnRH-I antagonist cetrorelix and of GnRH-II persist [41]. These ﬁndings suggest that the antiproliferative effects of cetrorelix and GnRH-II are not mediated through the type I GnRHR.

Over the last two decades, both GnRH agonists and antagonists have been widely used as therapeutics in treating sex steroid-dependent tumors. The majority these GnRH analogs, when given continuously, of inhibit gonadotropin synthesis and secretion via downregulation of the pituitary GnRHRs. This indi- rect mechanism of action has provided the rationale for the use of GnRH analogs in the treatment of hor- mone-dependent tumors for many years. Only since the detection of GnRHR in extrapituitary tissues has there been increasing interest in its direct action on tumor cells.

independent

GnRH-I has been demonstrated to have antiprolifer- ative effects on prostate cancer cells [49–51], except in one in vivo study [52]. This antiproliferative effect appears to be independent of the androgen receptor status of the prostate carcinoma cells, as both andro- gen-sensitive LNCaP cells and androgen-resistant DU-145 cells remain sensitive to GnRH [49,50]. Acti- vation of GnRHR may mediate these effects via direct induction of apoptosis through caspase activation [53]. Compatible with a role for GnRH in survival at low doses, an enhancing effect of GnRH was observed when cells were treated with a low concentration (100 pm) of GnRH-I agonist [54]. GnRH-II was shown to have an antiproliferative effect on DU-145 cells and growth-stimulatory effect on TSU-Pr1 cells, but the type I GnRHR was not involved [55].

GnRH-I analogs have direct antiproliferative effects on ovarian cancer cells, which is linked to the disrup- tion of the cell cycle at G0 ⁄ G1 [31,35,36]. On the other in vitro studies failed to hand, several demonstrate signiﬁcant growth inhibition by GnRH-I agonists, even at fairly high concentrations (micromolar range) [37,38]. In fact, a biphasic impact of GnRH-I agonists on growth has been reported: whereas GnRH-I agonists at high dose (1 lm) inhibit cell proliferation in vitro, cells treated with agonists at low dose (10 nm) show signiﬁcant growth stimulation [39]. Further studies demonstrated that nanomolar concentrations of GnRH-I agonists also increase cell survival under multiple stress conditions, including DNA replication- cytotoxic agents and UV radiation [40]. speciﬁc

The inﬂuence of GnRH on the growth of human breast cancer cells was ﬁrst studied with MCF-7 cells [56], and both in vitro and in vivo proliferation of

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GnRH-I and GnRH-II on cell invasion supports the view that the same receptor, type I GnRHR, is essen- tial for the effects of GnRH-I and GnRH-II in ovarian cancer cells.

breast cancer cells could be inhibited by both agonistic and antagonistic analogs of GnRH [57,58]. However, higher efﬁciency of GnRH antagonists in growth inhi- bition than that of GnRH agonists has been reported [24,58].

Invasion and metastasis

expression of

several

the

inhibitor

The observation that GnRH controls tumor growth suggests a regulatory role for this peptide in the meta- static behavior of cancer cells. This hypothesis is sup- ported by studies showing that GnRH-I and GnRH-II extracellular can affect matrix-degrading enzymes in human extravillous cyto- trophoblasts and decidual stromal cells to facilitate implantation [59,60]. However, its potential role in cancer metastasis has just begun to be revealed.

The decrease in uPA activity of cytosol from Dun- ning R3327H rat prostate tumors after treatment with GnRH-I analogs suggests that GnRH may be an important factor in reducing the invasiveness of pros- tate cancer [63]. High doses of GnRH-I agonists and antagonists have been reported to attenuate the invading capacity of both androgen-dependent and androgen-independent prostate cancer cells by modu- lating E-cadherin-mediated cell–cell contacts and pro- duction of uPA and its (plasminogen activator inhibitor-1) [64–66]. GnRH has also been shown to regulate cell motility through its interaction with the small GTPases Rac1, Cdc42, and RhoA, which are involved in the regulation of actin polymer- ization [67].

several

(uPA)

Metastasis is a complex phenomenon that requires several speciﬁc steps, such as decreased adhesion, increased motility, and proteolysis. The effects of GnRH in tumor metastasis are mediated through the regulation of adhesion molecules, Rho GTPases, and two families of metastasis-related proteinases, the matrix metallopro- teinases (MMPs) and the urokinase-type plasminogen activator levels: mRNA system, at transcription, secretion, and proenzyme activation.

treatment of

triptorelin,

the ability of melanoma cells

Up to now, there has been only one study, by Von Alten et al., investigating the role of GnRH in breast cancer metastasis, using a coculture system with human osteosarcoma cells to analyze tumor cell invasion to bone [68]. The consequences of GnRHR activation are complex and appear to be cell context cells with the dependent: whereas GnRH-I agonist the GnRH-II agonist [d-Lys6]GnRH-II and the GnRH-I antagonist cetrorelix decreases the invasion rate in most breast cancer cell lines, these agents have no signiﬁcant effect in the GnRHR-positive MDA-MB-435 cells [68]. Further investigations are required to elucidate the reason why the MDA-MB-435 cell line reacts differently.

The ability of GnRH to regulate metastasis was ﬁrst reported in melanoma cells [61]. High doses of GnRH-I signiﬁcantly analog, at micromolar concentrations, to invade reduces and migrate [61]. Preliminary data (R. M. Moretti, M. Monagnani Marelli, J. C. van Groeninghen, M. Motta & P. Limonta, unpublished results, 2003) indicate that this inhibitory action is due to the effects of integrins and MMPs [62].

Organ-speciﬁc homing and colonization of cancer cells are important and interesting features of metasta- sis. A role for GnRH has also been suggested in the regulation of the immune response and metastasis. GnRH-I and GnRH-II are expressed in human normal and cancerous T-cells. GnRH triggers laminin receptor gene expression, adhesion to laminin, in vitro chemo- taxis, and in vivo homing to speciﬁc organs [69].

Angiogenesis

such as

We were the ﬁrst to report possible metastatic activ- ity of GnRH-I in tumors of the female reproductive tract [12]. GnRH-I exerts a biphasic effect on cellular migration and invasion: whereas lower (nanomolar) concentrations of the GnRH-I agonist stimulate cellu- lar migration and invasion in a dose-dependent man- ner, high (micromolar) concentrations are not as efﬁcient. This proinvasive effect is mediated through activation of metastasis-related proteinases, in particu- lar MMP-2 and MMP-9 [12]. Moreover, GnRH-I is able to transactivate the MMP-2 and MMP-9 promot- ers, which means that GnRH can be considered to be a new member of MMP-2 and MMP-9 transcriptional modulators. Like GnRH-I, native GnRH-II and its synthetic analog also induce a similar biphasic regula- tion of ovarian cancer invasion [13]. The ﬁnding that small interfering RNA-mediated downregulation of type I GnRHR completely reversed the effects of both

Angiogenesis is crucial to a number of physiological and pathological processes, reproduction, development, and tissue repair, as well as tumor growth and metastasis. Vascular endothelial growth factor (VEGF) is implicated as the most important angiogenesis inducer, because of its potency in a variety of normal and tumor cells. Other angiogenic factors include ﬁbroblast growth factor (FGF), plate- let-derived growth factor and the angiopoietin family.

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very interesting to determine whether GnRH also plays a key role in tumor angiogenesis.

Intracellular signal transduction

Upon GnRH binding, GnRHR undergoes a conforma- tional change and stimulates a unique G-protein. Inter- estingly, the classical Gaq–11-phospholipase C signal transduction pathway, which is known to operate in the pituitary, is not involved in the antitumor activity of GnRH analogs. Rather, GnRHRs couple to Gai in these tumors and result in the activation of several downstream signaling cascades [73,74], such as mito- gen-activated protein kinase (MAPK), phosphatidyl- inositol-3-kinase (PI3K), and nuclear factor kappa B (NF-jB) signaling. The GnRH-induced signaling path- ways in extrapituitary tissues are shown schematically in Fig. 1.

The effect of GnRH on angiogenesis in the ovary, in which this neovascularization is necessary for follicular and luteal function, has been demonstrated. A recent in vivo study using rats revealed that an application of the GnRH-I agonist leuprolide acetate decreases the protein expression of VEGF and angiopoietin-1 and their receptors in ovarian follicles, and that this can be reversed by coinjection of the GnRH antagonist antide [70]. A similar inhibitory effect on angiogenesis can be observed in marmosets injected with the GnRH-I antagonist antarelix [71]. However, VEGF mRNA expression is unaffected by the treatment. The clinical response of uterine shrinkage after GnRH analog treatment and a pathological role of FGF-2, VEGF and platelet-derived growth factor in uterine leiomy- oma growth and vascularization has also been sug- is an gested [72]. Considering that angiogenesis important process in many human cancers, it would be

Fig. 1. Schematic representation of GnRHR signaling in extrapituitary tissues. Binding of GnRH to GnRHR triggers several intracellular signal- ing cascades and cross-talk with mitogenic signaling, depending on the cell context. Some of these signaling modules can transduce extra- cellular signals to the nucleus and thereby regulate genes that are involved in cell growth, metastasis, or survival. Arr, b-arrestin; CREB, cAMP response element-binding protein; FGFR, ﬁbroblast growth factor receptor; HB-EGF, heparin-binding EGF; IjB, inhibitory factor kap- pa B; IGFR, IGF receptor; MEK, mitogen-activated protein kinase kinase; MLK3, mixed-lineage kinase 3; PTP, protein tyrosine phosphatase; Sos, son of sevenless; TNF-a, tumor necrosis factor alpha.

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MAPK

receptor-interacting proteins

(Fig. 1).

implicated in nerve growth factor-mediated neuronal differentiation of PC12 cells, whereas a rapid and transient activation is associated with growth factor- mediated proliferation of PC12 cells [80]. Thus, the duration of kinase activation seems to be a major determinant of signal outcome. We have shown differ- ential regulation of ERK1 ⁄ 2, p38 MAPK, and JNK by GnRH-I with sustained signaling through the JNK pathway in ovarian cancer cells [12]. Consistently, GnRH-stimulated MMP-2 and MMP-9 expression, secretion and cell invasion were attenuated by speciﬁc inhibition of JNK but not of ERK1 ⁄ 2 and p38 MAPK, suggesting that prolonged activation of JNK may contribute to a more invasive phenotype. Strong and sustained activation of MAPK has been reported to be necessary for its cytoplasm-to-nucleus transloca- tion, and thereby contributes to the regulation of gene expression [79,81]. It will be interesting to see whether sustained activation of JNK leads to its nuclear trans- location, which is required for GnRH-stimulated cell invasion. The JNK pathway targets multiple transcrip- including c-Jun, c-Fos, ATF and PEA, tion factors, and putative binding sites for these DNA-binding pro- teins are present in the MMP promoters [82]. Whether these putative regulatory elements participate in the the MMP-2 and GnRH-dependent activation of MMP-9 genes remains to be determined.

Cross-talk with mitogenic signaling

is now receiving further

to activate ERK1 ⁄ 2,

Cross-talk between cell surface receptors, which has been recognized as a mechanism capable of generating signal diversity, interest. Figure 1 illustrates the cross-talk between GnRHR and receptor tyrosine kinases (RTKs). For instance, GnRH causes transactivation of RTKs, such as EGFR [75,78,83]. MMP-2 and MMP-9 seem to be essential for GnRH-induced EGFR activation by cleavage of the heparin-binding epidermal growth factor (EGF) precursor [84]. Transactivation of EGFR has been shown as GnRH-induced ERK1 ⁄ 2 phosphorylation can be abolished in the pres- ence of the EGFR inhibitor AG1478 [53,78]. However, the biological importance of ERK1 ⁄ 2 activation in response to this cross-talk still remains elusive.

The major MAPK cascades include extracellular sig- nal-regulated kinase (ERK), Jun N-terminal kinase (JNK), and p38 MAPK. Many studies have shown that the MAPK pathway is critical for GnRH activi- ties, which provides an important link for the trans- mission of signals from the cell surface to the nucleus. Activation of MAPK by GnRH involves distinct upstream pathways in generating tissue-speciﬁc and cell-speciﬁc signaling (Fig. 1). This can occur at differ- ent levels via different mechanisms: (a) second messen- [26]; [protein kinase C (PKC) and cAMP] gers (b) such as Src and b-zarrestin [53,75]; and (c) upstream kinases such as MAPK ⁄ ERK kinase and PI3K [53,76]. For example, GnRH-I induces apoptosis in DU-145 prostate cancer cells via JNK, which is activated through two indepen- dent mechanisms [53]. Activation of the pathway is dependent on c-Src with concomitant decrease in Akt activity, and the combination of these two events relieves the inhibition of the upstream activator of JNK, MLK3 [53] Interestingly, although ERK1 ⁄ 2 is phosphorylated through epidermal growth factor receptor (EGFR) under the same conditions, this pathway is not involved in the apoptotic effects. These ﬁndings demonstrate that activation of the two MAPKs, which lead to distinct physiological out- comes, is separated already at the upstream levels. In the ovarian cancer cell line CaOV-3, prolonged stimu- lation of ERK1 ⁄ 2 through Shc and son of sevenless is required for GnRH-I-mediated growth inhibition [76]. Consistent with the fact that sustained activation of ERK1 ⁄ 2 is often correlated with cell cycle progression, GnRH-I-induced growth inhibition is attributed to G1 arrest [76]. Moreover, the signaling cascade was shown to be initiated by Gbc, supporting the notion that the post-GnRHR signaling cascade in extrapituitary cells is different from that in pituitary cells. GnRH-induced MAPK activation has also been shown in another ovarian cancer cell line, OVCAR-3. Both ERK1 ⁄ 2 and p38 MAPK mediate the antiproliferative effects of GnRH-I and GnRH-II in a PKC-dependent manner [43,77]. GnRH-II induces the activation of activator protein-1 transcription factor via p38 MAPK, suggest- ing a potential role of activator protein-1 in ovarian cancer cell growth [77]. The JNK pathway also drives tumor invasion and migration in ovarian cancer cells [12], but the activation mechanism(s) remains to be elucidated.

signaling

adhesive

Negative cross-talk between GnRHR and growth factor receptors has also been described. For instance, the antiproliferative effects of GnRH-I and GnRH-II agonists are mediated through attenuation of EGFR signaling in many reproductive tumor cells [57,66,85– 87]. In prostate cancer cells, cetrorelix is able to coun- ter EGFR-dependent through a PKC-dependent mechanism [66]. Activation of

Temporal and spatial differences in cellular signaling may have signiﬁcant phenotypic manifestations [78,79]. For example, sustained activation of ERK1 ⁄ 2 has been

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[95]. These data suggest

tor has no effect on the activation of NF-jB [94]. It has also been shown that GnRH-I suppresses interleu- kin-8 expression via attenuation of tumor necrosis fac- tor alpha-induced NF-jB signaling in endometriotic that stromal cells (Fig. 1) modulation of cytokine signal transduction by GnRH may be one of the mechanisms contributing to its growth-inhibitory effect.

reorganization.

GnRHR appears to mediate these effects via activation of phosphotyrosine phosphatase, thereby reducing EGF-induced EGFR autophosphorylation, resulting in downregulation of mitogenic signal transduction and cell proliferation [85,86,88]. A negative regulatory interaction between GnRHR and mitogenic signaling pathways has also been reported in human prostate cancer cells via insulin-like growth factor. GnRH-I agonists inhibit expression of the insulin-like growth factor receptor, receptor tyrosine phosphorylation, and the subsequent downstream activation of Akt [89–91]. Another example is FGF-2. GnRH analog treatment has been shown to block cell proliferation and inva- sion induced by FGF-2 stimulation [65].

PI3K

The non-RTKs focal adhesion kinase (FAK) and proline-rich tyrosine kinase 2 (Pyk2) are the predomi- nant mediators of integrin signaling. GnRHR has been shown to signal through these molecules, suggesting a In role for GnRH in cytoskeletal human endometrial cancer cells (HEC-1A), b3-integrin- dependent activation of FAK is associated with the inhibitory effects of GnRH-I and GnRH-II on growth [96]. Leiomyoma regression induced by GnRH-I agon- ists has been suggested to be mediated, at least in part, through a mechanism involving suppression of FAK [97]. Maudsley et al. demonstrated a novel signaling cascade of GnRHR that functionally antagonizes the testosterone and inhibits prostate tumor actions of growth [98]. GnRH controls the tyrosine phosphoryla- tion status of the focal adhesion proteins Pyk2 and Hic-5. This alteration of the focal adhesion dynamics then results in nuclear translocation of the androgen receptor, which renders it transcriptionally inactive [98].

The PI3K signaling pathway and its downstream target Akt (also named protein kinase B) has been implicated in promoting cell survival, proliferation, and invasion. In uterine leiomyomas, the GnRH-I ago- nist leuprolide acetate causes a signiﬁcant reduction in PI3K ⁄ Akt activity and inhibits the expression of the antiapoptotic proteins (c-FLIP and PED ⁄ PEA15), thereby inducing apoptosis [92]. In the SKOV-3 ovar- ian cancer cell line, GnRH-I and GnRH-II interfere with activation of the PI3K ⁄ Akt cascade, and this is is associated with the inhibitory effects of GnRH on cell invasion [13].

Mechanisms underlying the diverse responses to GnRH action

in prostate

cells,

[12,13,39]. Moreover,

Although PI3K ⁄ Akt and MAPK are two parallel pathways in some cell types, they are two related path- ways in the mediation of GnRH actions, as inhibition of PI3K ⁄ Akt can alter the activation of MAPK. For stimulation of cancer instance, PI3K ⁄ Akt releases mixed-lineage kinase 3, which in turn activates the JNK pathway, and this positive reg- ulation is important for the proapoptotic effect of GnRH-I (Fig. 1) [53]. PI3K ⁄ Akt is also an upstream kinase of ERK1 ⁄ 2, and EGFR transactivation by GnRH-I may be required for the activation of this cascade [75,93].

Other signaling pathways

signaling pathways

studied,

Activation of NF-jB is important for the protection against apoptosis in ovarian tumors induced by the GnRH-I agonist tiptorelin [94]. The effect is probably mediated by the Gai-coupled GnRHR, and receptor activation causes nuclear translocation of NF-jB [94]. Unlike the other the GnRH-I-induced NF-jB activation appears to be inde- pendent of the cross-talk between GnRHR and growth factor signaling, as treatment with phosphatase inhibi-

As discussed earlier, GnRH and its agonists have a dual and biphasic action: whereas low concentrations (0.1–10 nm) of GnRH stimulate cell proliferation, migration and invasion in a dose-dependent manner, high concentrations (100 nm to 1 lm) these inhibit the same dose of functions GnRH can elicit completely opposite responses in cells derived from the same tissue. We demonstrated that in two human ovarian cancer cell lines, OVCAR-3 and SKOV-3, GnRH-I and GnRH-II induce invasion of OVCAR-3 cells, but inhibit the invasiveness of SKOV- 3 cells [13]. A similar difference has been found in the effects of GnRH on cell proliferation and cell migra- tion in the prostate carcinoma cell lines TSU-Pr1 and DU-145 [67]. Whereas GnRH-I and GnRH-II stimu- lated cell proliferation, induced actin cytoskeleton remodeling and promoted migration in TSU-Pr1 cells, they were inhibitory in DU-145 cells [67]. The observa- tion that GnRH-I and GnRH-II have no signiﬁcant effect in cell lines with type I GnRHR depletion indi- cates that the type I GnRHR is indispensable for the

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Table 1. Potential mechanisms that underlie the diverse responses to GnRH.

Determinants

References

[99–101]

for dual

Treatment conditions, e.g. duration and dose Different Ga subtypes Different G-protein subunits GnRHR expression level Ligand selectivity Presence of GnRHR splice variants Intrinsic cellular properties

[73,74,101,103,104] [105–109] [6,110–112] [114,115] [118,119] [61,62]

Third, multiple GnRH-dependent signaling path- ways may occur via different subunits of a single G-protein [105]. After ligand-induced dissociation, both the a-subunit and bc-subunits are capable of activating various effectors, such as adenylyl cyclase, phospholipase C, and ion channels, thereby conferring on the receptor signaling the potential [106,107]. The effector pathway to be activated is instance, to the upstream subunits. For speciﬁc whereas the a-subunit of Gi inhibits adenylyl cyclase activity, the bc-subunits may stimulate the activities of some adenylyl cyclase subtypes [108,109].

The receptor expression level is also known to be a determinant for different signal outcomes [6,110,111]. In gonadotropes, different cell surface densities of GnRHR result in the differential regulation of luteiniz- ing hormone and follicle-stimulating hormone subunit gene expression by GnRH-I [112]. We and others have previously shown that low doses of GnRH upregulate the expression of its receptor, whereas high doses decrease it [12,111,113]. This difference in regulation suggests that high levels of GnRHR expression may enhance the cellular response to GnRH stimulation, presumably due to more efﬁcient signal ampliﬁcation or altered signaling through coupling to different G-proteins.

Moreover,

effects of both GnRH-I and GnRH-II [13,67]. Thus, one intriguing question is how a common GnRHR may mediate different, even opposite, responses to GnRH in the same cell type ⁄ tissue. The reasons are unknown, but several possibilities (as summarized in Table 1) can be envisaged. First, the treatment condi- tion may be one determinant of the outcome. The pulsatility of GnRH release is necessary for the hor- mone to stimulate pituitary gonadotropes. On the other hand, sustained administration of the peptide brings about a short initial stimulation that is rapidly followed by a decrease in gonadotropin synthesis and secretion [99]. In support of this, the signal response is different at different doses. It has been shown that pul- satile GnRH stimulates more sustained ERK activity (more than 8 h), whereas continuous infusion of aT3-1 cells with GnRH stimulates short-term (2 h) ERK activity [100]. There is also evidence that GnRH treat- ment stimulates cAMP production at nanomolar con- centrations, but has an inhibitory effect at micromolar concentrations [101]. It should be pointed out that the nanomolar concentration (0.01–1 nm) corresponds to the physiological circulating level, and the effects caused by this dose range may represent the physiolog- ical functions of GnRH [54,102].

ligand selectivity has been proposed to explain the opposite (stimulatory and inhibitory) effects of GnRH. For instance, in positively respond- lines, GnRH-I is more ing prostate carcinoma cell effective than GnRH-II. On the other hand, in nega- tively responding cell lines, GnRH-II is much more effective than GnRH-I. Given the short plasma half- life of GnRH, efforts have been made to obtain GnRH analogs, to resist degradation and to increase potency. However, the different GnRH agonists may selectively stabilize different receptor-active conforma- tions and therefore different ligand-induced selective signaling pathways [114]. In this regard, it has been shown that the highly variable amino acid at posi- tion 8 of GnRH plays a discriminating role in selecting the receptor conformational state [115].

Second, GnRH action has been shown to be medi- ated by coupling to different Ga-proteins, depending on the time and dose of exposure [101,103]. In general, Gaq and Gas are associated with a stimulatory effect [103], whereas Gai often mediates the antiproliferative and proapoptotic effects of GnRH [73,74]. Low GnRH concentrations promote the coupling of GnRHR to [101]. High concentrations of GnRH cause a Gas switch in receptor coupling from Gas to Gai [101]. Moreover, stimulation of cAMP production by GnRH is through coupling to Gas, whereas inhibition of cAMP production at high concentrations of GnRH is through coupling to Gai [101,104]. These ﬁndings sug- gest that the intracellular milieu in different tissues results in differential coupling and different phenotypic effects.

The presence of splice variants of the GnRHR tran- script may be another possible reason for the different or opposite responses to GnRH. To date, variant tran- scripts of GnRHR have been isolated in many species, e.g. chicken [116], mouse [117] and human [118]. Although these splice variants are totally incapable of ligand binding or signal transduction, they have been implicated in the functional regulation of the wild-type receptor. Previous studies have reported their inhibi- tory activity on full-length GnRHR function [119]. This inhibition is speciﬁc, augmented by increasing

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s e c n e r e f e R

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amounts of the cotransfected splice variant cDNA and possibly by preventing or diverting the normal process- ing of GnRHR or enhancing GnRHR degradation [118].

Finally,

that differences

is also possible

invasive effect

tor that is not rapidly desensitized or internalized. There is evidence that GnRH-II may act through the type I GnRHR. In monkey pituitary cultures, in which the type II GnRHR is functional, GnRH-II has been found to stimulate gonadotropin secretion exclusively through the type I GnRHR [146]. In contrast, other evidence suggests that the neuromodulatory action of GnRH-II on mammalian behavior is not mediated via it the type I receptor in musk shrews [147]. Thus, appears that GnRH-II may selectively interact with different GnRHRs to mediate its different actions, pre- sumably due to the structural differences between the two GnRHR subtypes.

in response may be ascribed to the intrinsic properties of the cells. The physiological characteristics of the human cancer cell lines mentioned in this minireview are summarized in Table 2. For example, in contrast to SKOV-3 cells, OVCAR-3 cells have low invasive potential. Thus, whereas low doses of GnRH-I and GnRH-II can exert a signiﬁcant in OVCAR-3 cells, they fail to stimulate SKOV-3 maxi- mally [12,13]. Both GnRH-I and GnRH-II only exert inhibitory effects on SKOV-3 cells at high doses [13].

Novel receptor(s) for GnRH in humans?

functional,

Alternatively, it is possible that the human type II GnRHR may be encoded by a different gene that has yet to be identiﬁed. Database searches have revealed the presence of more than two other GnRHR genes in the human genome apart from the conventional type I receptor gene [148]. These genes are located on sepa- rate chromosomes. Whether full-length transcripts can be produced from these receptor-like genes remains to be determined. Recently, a novel GnRH-II-binding protein, in addition to a conven- tional GnRHR, has been identiﬁed by using photo- afﬁnity labeling with an azidobenzoyl-conjugated GnRH-II in prostate cancer cells [149]. Taken together, these observations thus suggest the potential existence of novel receptors for GnRH-I and GnRH-II.

Concluding remarks

(positive

even opposite

studies

further

cross-talk. Clearly,

An important issue that remains unresolved in this ﬁeld is whether one or more other GnRHR subtypes exist in humans. The discovery of GnRH-II has stimu- lated the search for a cognate type II GnRHR. Molec- ular cloning of the type II GnRHR in goldﬁsh, marmoset and monkey has shown that the type II receptor is structurally and functionally distinct from the type I receptor [138–140]. In humans, a type II GnRHR has not been found. However, a search of the revealed a putative human genome database has type II GnRHR gene chromosome 1q21.1 on [140,141]. Expression of this type II GnRHR mRNA has been shown in many human tissues, including endometrium, ovary, placenta, and prostate cancer cells [42,55,140–142]. Although these ﬁndings suggest that the human type II receptor gene is transcription- ally active, the mRNA is disrupted by a frameshift in coding exon 1 and a premature stop codon in exon 2, suggesting that a conventional seven-transmembrane receptor cannot be translated from this gene. The gene also overlaps two ﬂanking genes and displays alterna- tive splicing [143]. Thus, the functionality of these human type II GnRHR splice variants and their involvement in transmitting signals from GnRH-II are still in question.

One noteworthy feature of

This overview shows that GnRH modulates a variety of cellular functions in extrapituitary tissues, such as cell growth, invasion, and angiogenesis. However, the effects of GnRH are complex and appear to be cell context dependent. The ability of GnRH to elicit very different, and negative), responses in extrapituitary tissues may arise from dif- ferential usage of signal transduction pathways and receptor are required to unravel this complex signaling network and the coordinated regulatory roles of different factors in speciﬁc cellular events during tumorigenesis. High-throughput gene proﬁling and bioinformatics approaches should be helpful to expand this area of research. The information may also serve as a basis for investigators in the ﬁeld to explore the signaling mechanisms of other G-protein-coupled receptors. Most studies thus far have only been conducted in cellular models, but in vivo approaches will be essential for a complete understanding of the speciﬁc role of each GnRH isoform, including the putative GnRH-III isolated from the human brain [150]. Given the clinical

the primate type II GnRHR is that, unlike the type I receptor, it possesses a C-terminal tail, which is responsible for the recep- tor’s susceptibility to rapid desensitization and inter- nalization [138,144,145]. Finch et al. showed that GnRH was able to efﬁciently inhibit the proliferation of breast cancer cells when engineered with sheep type I GnRHR, but not with Xenopus type II GnRHR [145]. This clearly implies that the antiproliferative effect of GnRH is mediated most efﬁciently by a recep-

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utility of GnRH analogs in hormone-dependent dis- eases, better characterization of GnRH actions and its key molecular effectors is a necessary ﬁrst step to more effective and perhaps new therapeutic strategies for improving clinical outcome.

mone binding sites in human epithelial ovarian carci- nomata. Eur J Cancer Clin Oncol 25, 215–221. 11 Chien CH, Chen CH, Lee CY, Chang TC, Chen RJ &

Chow SN (2004) Detection of gonadotropin-releasing hormone receptor and its mRNA in primary human epithelial ovarian cancers. Int J Gynecol Cancer 14, 451–458.

Acknowledgements

This work was supported by the Hong Kong Research Grant Council grant 778108 to A. S. T. Wong.

12 Cheung LW, Leung PC & Wong AS (2006) Gona-

dotropin-releasing hormone promotes ovarian cancer cell invasiveness through c-Jun NH2-terminal kinase- mediated activation of matrix metalloproteinase (MMP)-2 and MMP-9. Cancer Res 66, 10902– 10910.

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Báo cáo khoa học: Gonadotropin-releasing hormone: GnRH receptor signaling in extrapituitary tissues

M I N I R E V I E W

Gonadotropin-releasing hormone: GnRH receptor signaling in extrapituitary tissues Lydia W. T. Cheung and Alice S. T. Wong

Introduction

Localization of GnRH receptor (GnRHR) in peripheral reproductive tissues

Functions of GnRH-I and GnRH-II in cancers

Intracellular signal transduction

Mechanisms underlying the diverse responses to GnRH action

Novel receptor(s) for GnRH in humans?

Concluding remarks

Acknowledgements

References

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