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Role of gonadotropin-releasing hormone (GnRH) in ovarian cancer.

Gründker C, Emons G - Reprod. Biol. Endocrinol. (2003)

Bottom Line: The proliferation of these cells is dose- and time-dependently reduced by GnRH-II in a greater extent than by GnRH-I (GnRH, LHRH) superagonists.In addition, in the ovarian cancer cell line EFO-27 GnRH-I receptor but not putative GnRH-II receptor expression was found.These data suggest that in ovarian cancer cells the antiproliferative effects of GnRH-I antagonist Cetrorelix and GnRH-II are not mediated through the GnRH-I receptor.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Gynecology and Obstetrics, Georg-August-University, Robert-Koch-Street 40, D-37075 Göttingen, Germany. grundker@med.uni-goettingen.de

ABSTRACT
The expression of GnRH (GnRH-I, LHRH) and its receptor as a part of an autocrine regulatory system of cell proliferation has been demonstrated in a number of human malignant tumors, including cancers of the ovary. The proliferation of human ovarian cancer cell lines is time- and dose-dependently reduced by GnRH and its superagonistic analogs. The classical GnRH receptor signal-transduction mechanisms, known to operate in the pituitary, are not involved in the mediation of antiproliferative effects of GnRH analogs in these cancer cells. The GnRH receptor rather interacts with the mitogenic signal transduction of growth-factor receptors and related oncogene products associated with tyrosine kinase activity via activation of a phosphotyrosine phosphatase resulting in downregulation of cancer cell proliferation. In addition GnRH activates nucleus factor kappaB (NFkappaB) and protects the cancer cells from apoptosis. Furthermore GnRH induces activation of the c-Jun N-terminal kinase/activator protein-1 (JNK/AP-1) pathway independent of the known AP-1 activators, protein kinase (PKC) or mitogen activated protein kinase (MAPK/ERK). Recently it was shown that human ovarian cancer cells express a putative second GnRH receptor specific for GnRH type II (GnRH-II). The proliferation of these cells is dose- and time-dependently reduced by GnRH-II in a greater extent than by GnRH-I (GnRH, LHRH) superagonists. In previous studies we have demonstrated that in ovarian cancer cell lines except for the EFO-27 cell line GnRH-I antagonist Cetrorelix has comparable antiproliferative effects as GnRH-I agonists indicating that the dichotomy of GnRH-I agonists and antagonists might not apply to the GnRH-I system in cancer cells. After GnRH-I receptor knock down the antiproliferative effects of GnRH-I agonist Triptorelin were abrogated while the effects of GnRH-I antagonist Cetrorelix and GnRH-II were still existing. In addition, in the ovarian cancer cell line EFO-27 GnRH-I receptor but not putative GnRH-II receptor expression was found. These data suggest that in ovarian cancer cells the antiproliferative effects of GnRH-I antagonist Cetrorelix and GnRH-II are not mediated through the GnRH-I receptor.

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GnRH-I and GnRH-II signaling in human gynecological cancer cells: A) GnRH-I activates a phosphotyrosine phosphatase (PTP) inhibiting the mitogenic signal transduction of growth factor receptors resulting in downregulation of cell proliferation. B) GnRH-I downregulates epidermal growth factor (EGF) receptor mRNA expression. C) Activated GnRH-I receptor induces nucleus factor κB (NFκB) activation and nuclear translocation of activated NFκB. Activated NFκB now couples to κB DNA binding sites and induces expression of anti-apoptotic mechanisms. D) GnRH-I activates c-Jun N-terminal kinase (JNK), induces JunD-DNA binding and stimulates activator protein (AP-1) activity, resulting in reduced proliferation as indicated by increased G0/1 phase of cell cycle and decreased DNA synthesis. E) Unknown signal transduction of a putative human GnRH-II receptor. In human gynecological cancer cells GnRH-I analogs mediate antiproliferative actions via inhibition of growth factor-induced mitogenic signal transduction. In addition GnRH-I induces growth factor receptor downregulation. GnRH-I protects the cancer cells from apoptosis via activation of NFκB, stimulates AP-1 activity and extends cell cycle. PPTK, receptor protein tyrosine kinase; GRB2, adaptor protein; SOS, guanine nucleotide exchange factor; RAS, small GTPase; RAF, a protein-serine/threonine kinase; MAPK-K, mitogen activated kinase kinase; MAPK, mitogen activated kinase; TCF, transcription factor; IκB, inhibitory κB; Gq, G-protein αq; Gi, G-protein αi; p50, p65, NFκB subunits.
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Figure 1: GnRH-I and GnRH-II signaling in human gynecological cancer cells: A) GnRH-I activates a phosphotyrosine phosphatase (PTP) inhibiting the mitogenic signal transduction of growth factor receptors resulting in downregulation of cell proliferation. B) GnRH-I downregulates epidermal growth factor (EGF) receptor mRNA expression. C) Activated GnRH-I receptor induces nucleus factor κB (NFκB) activation and nuclear translocation of activated NFκB. Activated NFκB now couples to κB DNA binding sites and induces expression of anti-apoptotic mechanisms. D) GnRH-I activates c-Jun N-terminal kinase (JNK), induces JunD-DNA binding and stimulates activator protein (AP-1) activity, resulting in reduced proliferation as indicated by increased G0/1 phase of cell cycle and decreased DNA synthesis. E) Unknown signal transduction of a putative human GnRH-II receptor. In human gynecological cancer cells GnRH-I analogs mediate antiproliferative actions via inhibition of growth factor-induced mitogenic signal transduction. In addition GnRH-I induces growth factor receptor downregulation. GnRH-I protects the cancer cells from apoptosis via activation of NFκB, stimulates AP-1 activity and extends cell cycle. PPTK, receptor protein tyrosine kinase; GRB2, adaptor protein; SOS, guanine nucleotide exchange factor; RAS, small GTPase; RAF, a protein-serine/threonine kinase; MAPK-K, mitogen activated kinase kinase; MAPK, mitogen activated kinase; TCF, transcription factor; IκB, inhibitory κB; Gq, G-protein αq; Gi, G-protein αi; p50, p65, NFκB subunits.

Mentions: During the last ten years, the signaling mechanisms mediating the antiproliferative effects of GnRH-I analogs in ovarian, endometrial and breast cancer cells have been elucidated. The signaling mechanism of GnRH-I receptor in human cancers is quite different from that in pituitary gonadotrophs, where GnRH-I receptors couple to G-protein αq and activate phospholipase C (PLC), protein kinase C (PKC), and adenylyl cyclase (AC) [reviewed in [4]]. Although we could clearly demonstrate the activation of PLC, PKC, and AC in these tumor cells by pharmacological stimuli [35], the signaling pathways induced by GnRH-I in pituitary gonadotrophs were not activated by GnRH-I agonist Triptorelin in ovarian, endometrial and breast cancer cell lines [35,36]. We found, however, that after binding of its ligand, the GnRH-I receptor in these cancers couples to G-protein αi and activates a phosphotyrosine phosphatase (PTP) [35-40] (Fig. 1A). This PTP dephosphorylates EGF receptors [36]. As a result, mitogenic signaling induced by EGF binding to its receptor is abrogated leading to a suppression of EGF-induced activation of mitogen-activated protein kinase (MAPK) [35], c-fos expression [41], and EGF-induced proliferation [35] (Fig. 1A). These findings are in accord with reports that GnRH-I analogs reduce expression of growth factor receptors and their mRNA [12,42,43] (Fig. 1B) and/or growth factor induced tyrosine kinase activity [35,37-39,42,44-46]. The reason for the differences of the GnRH-I receptor signaling between pituitary gonadotrophs and tumor cells remains unclear, as we could not find mutations or splice variants in the tumor GnRH-I receptor which might explain this phenomenon.


Role of gonadotropin-releasing hormone (GnRH) in ovarian cancer.

Gründker C, Emons G - Reprod. Biol. Endocrinol. (2003)

GnRH-I and GnRH-II signaling in human gynecological cancer cells: A) GnRH-I activates a phosphotyrosine phosphatase (PTP) inhibiting the mitogenic signal transduction of growth factor receptors resulting in downregulation of cell proliferation. B) GnRH-I downregulates epidermal growth factor (EGF) receptor mRNA expression. C) Activated GnRH-I receptor induces nucleus factor κB (NFκB) activation and nuclear translocation of activated NFκB. Activated NFκB now couples to κB DNA binding sites and induces expression of anti-apoptotic mechanisms. D) GnRH-I activates c-Jun N-terminal kinase (JNK), induces JunD-DNA binding and stimulates activator protein (AP-1) activity, resulting in reduced proliferation as indicated by increased G0/1 phase of cell cycle and decreased DNA synthesis. E) Unknown signal transduction of a putative human GnRH-II receptor. In human gynecological cancer cells GnRH-I analogs mediate antiproliferative actions via inhibition of growth factor-induced mitogenic signal transduction. In addition GnRH-I induces growth factor receptor downregulation. GnRH-I protects the cancer cells from apoptosis via activation of NFκB, stimulates AP-1 activity and extends cell cycle. PPTK, receptor protein tyrosine kinase; GRB2, adaptor protein; SOS, guanine nucleotide exchange factor; RAS, small GTPase; RAF, a protein-serine/threonine kinase; MAPK-K, mitogen activated kinase kinase; MAPK, mitogen activated kinase; TCF, transcription factor; IκB, inhibitory κB; Gq, G-protein αq; Gi, G-protein αi; p50, p65, NFκB subunits.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC239893&req=5

Figure 1: GnRH-I and GnRH-II signaling in human gynecological cancer cells: A) GnRH-I activates a phosphotyrosine phosphatase (PTP) inhibiting the mitogenic signal transduction of growth factor receptors resulting in downregulation of cell proliferation. B) GnRH-I downregulates epidermal growth factor (EGF) receptor mRNA expression. C) Activated GnRH-I receptor induces nucleus factor κB (NFκB) activation and nuclear translocation of activated NFκB. Activated NFκB now couples to κB DNA binding sites and induces expression of anti-apoptotic mechanisms. D) GnRH-I activates c-Jun N-terminal kinase (JNK), induces JunD-DNA binding and stimulates activator protein (AP-1) activity, resulting in reduced proliferation as indicated by increased G0/1 phase of cell cycle and decreased DNA synthesis. E) Unknown signal transduction of a putative human GnRH-II receptor. In human gynecological cancer cells GnRH-I analogs mediate antiproliferative actions via inhibition of growth factor-induced mitogenic signal transduction. In addition GnRH-I induces growth factor receptor downregulation. GnRH-I protects the cancer cells from apoptosis via activation of NFκB, stimulates AP-1 activity and extends cell cycle. PPTK, receptor protein tyrosine kinase; GRB2, adaptor protein; SOS, guanine nucleotide exchange factor; RAS, small GTPase; RAF, a protein-serine/threonine kinase; MAPK-K, mitogen activated kinase kinase; MAPK, mitogen activated kinase; TCF, transcription factor; IκB, inhibitory κB; Gq, G-protein αq; Gi, G-protein αi; p50, p65, NFκB subunits.
Mentions: During the last ten years, the signaling mechanisms mediating the antiproliferative effects of GnRH-I analogs in ovarian, endometrial and breast cancer cells have been elucidated. The signaling mechanism of GnRH-I receptor in human cancers is quite different from that in pituitary gonadotrophs, where GnRH-I receptors couple to G-protein αq and activate phospholipase C (PLC), protein kinase C (PKC), and adenylyl cyclase (AC) [reviewed in [4]]. Although we could clearly demonstrate the activation of PLC, PKC, and AC in these tumor cells by pharmacological stimuli [35], the signaling pathways induced by GnRH-I in pituitary gonadotrophs were not activated by GnRH-I agonist Triptorelin in ovarian, endometrial and breast cancer cell lines [35,36]. We found, however, that after binding of its ligand, the GnRH-I receptor in these cancers couples to G-protein αi and activates a phosphotyrosine phosphatase (PTP) [35-40] (Fig. 1A). This PTP dephosphorylates EGF receptors [36]. As a result, mitogenic signaling induced by EGF binding to its receptor is abrogated leading to a suppression of EGF-induced activation of mitogen-activated protein kinase (MAPK) [35], c-fos expression [41], and EGF-induced proliferation [35] (Fig. 1A). These findings are in accord with reports that GnRH-I analogs reduce expression of growth factor receptors and their mRNA [12,42,43] (Fig. 1B) and/or growth factor induced tyrosine kinase activity [35,37-39,42,44-46]. The reason for the differences of the GnRH-I receptor signaling between pituitary gonadotrophs and tumor cells remains unclear, as we could not find mutations or splice variants in the tumor GnRH-I receptor which might explain this phenomenon.

Bottom Line: The proliferation of these cells is dose- and time-dependently reduced by GnRH-II in a greater extent than by GnRH-I (GnRH, LHRH) superagonists.In addition, in the ovarian cancer cell line EFO-27 GnRH-I receptor but not putative GnRH-II receptor expression was found.These data suggest that in ovarian cancer cells the antiproliferative effects of GnRH-I antagonist Cetrorelix and GnRH-II are not mediated through the GnRH-I receptor.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Gynecology and Obstetrics, Georg-August-University, Robert-Koch-Street 40, D-37075 Göttingen, Germany. grundker@med.uni-goettingen.de

ABSTRACT
The expression of GnRH (GnRH-I, LHRH) and its receptor as a part of an autocrine regulatory system of cell proliferation has been demonstrated in a number of human malignant tumors, including cancers of the ovary. The proliferation of human ovarian cancer cell lines is time- and dose-dependently reduced by GnRH and its superagonistic analogs. The classical GnRH receptor signal-transduction mechanisms, known to operate in the pituitary, are not involved in the mediation of antiproliferative effects of GnRH analogs in these cancer cells. The GnRH receptor rather interacts with the mitogenic signal transduction of growth-factor receptors and related oncogene products associated with tyrosine kinase activity via activation of a phosphotyrosine phosphatase resulting in downregulation of cancer cell proliferation. In addition GnRH activates nucleus factor kappaB (NFkappaB) and protects the cancer cells from apoptosis. Furthermore GnRH induces activation of the c-Jun N-terminal kinase/activator protein-1 (JNK/AP-1) pathway independent of the known AP-1 activators, protein kinase (PKC) or mitogen activated protein kinase (MAPK/ERK). Recently it was shown that human ovarian cancer cells express a putative second GnRH receptor specific for GnRH type II (GnRH-II). The proliferation of these cells is dose- and time-dependently reduced by GnRH-II in a greater extent than by GnRH-I (GnRH, LHRH) superagonists. In previous studies we have demonstrated that in ovarian cancer cell lines except for the EFO-27 cell line GnRH-I antagonist Cetrorelix has comparable antiproliferative effects as GnRH-I agonists indicating that the dichotomy of GnRH-I agonists and antagonists might not apply to the GnRH-I system in cancer cells. After GnRH-I receptor knock down the antiproliferative effects of GnRH-I agonist Triptorelin were abrogated while the effects of GnRH-I antagonist Cetrorelix and GnRH-II were still existing. In addition, in the ovarian cancer cell line EFO-27 GnRH-I receptor but not putative GnRH-II receptor expression was found. These data suggest that in ovarian cancer cells the antiproliferative effects of GnRH-I antagonist Cetrorelix and GnRH-II are not mediated through the GnRH-I receptor.

Show MeSH
Related in: MedlinePlus