Signal Transduction of GnRH Receptor in the Reproductive.

Imai, Atsushi; Horibe, Shinji; Takagi, Hiroshi; Fuseya, Tatsuo; Tamaya, Teruhiko

doi:10.1507/endocrj.43.249

Cited by 21 publications

(6 citation statements)

References 112 publications

(26 reference statements)

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“…In the authors' opinion, this is the first demonstration of the coupling of the LHRH receptor to the G␣ i -cAMP signal transduction pathway in prostate cancer, in addition to the identification of the molecular size of the LHRH receptor protein (see above). In line with the present data, Imai and co-workers (42) have recently reported that, in tumors of the human female reproductive tract, LHRH receptors are coupled to a 41-kDa G␣ i protein; these authors suggested that this protein might mediate the LHRH-induced phosphotyrosine phosphatase activity in tumor cells (42,43).…”

Section: Discussionsupporting

confidence: 91%

The Luteinizing Hormone-Releasing Hormone Receptor in Human Prostate Cancer Cells: Messenger Ribonucleic Acid Expression, Molecular Size, and Signal Transduction Pathway

Limonta¹

1999

Endocrinology

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Evidence has accumulated indicating that LHRH might behave as an autocrine/paracrine growth inhibitory factor in some peripheral tumors. However, LHRH receptors in tumor cells have not been fully characterized, so far. The present experiments were performed to analyze: 1) the messenger RNA expression; 2) the molecular size; and 3) the signal transduction pathway of LHRH receptors in prostate cancer. For these studies, the human androgen-dependent LNCaP and androgen-independent DU 145 prostate cancer cell lines were used. 1) By RT-PCR, a complementary DNA product, which hybridized with a 32P-labeled oligonucleotide probe specific for the pituitary LHRH receptor complementary DNA, was found both in LNCaP and in DU 145 cells. 2) Western blot analysis, using a monoclonal antibody raised against the human pituitary LHRH receptor, revealed the presence of a protein band of approximately 64 kDa (corresponding to the molecular mass of the pituitary receptor) in both cell lines. 3) In LNCaP and DU 145 cells, pertussis toxin completely abrogated the antiproliferative action of a LHRH agonist (LHRH-A). Moreover, LHRH-A substantially antagonized the pertussis toxin-catalyzed ADP-ribosylation of a Galpha(i) protein. Finally, LHRH-A significantly counteracted the forskolin-induced increase of intracellular cAMP levels in both cell lines. These data demonstrate that the LHRH receptor, which is present in prostate cancer cells, independently of whether they are androgen-dependent or not, corresponds to the pituitary receptor, in terms of messenger RNA expression and protein molecular size. However, at variance with the receptor of the gonadotrophs, prostate cancer LHRH receptor seems to be coupled to the Galpha(i) protein-cAMP signal transduction pathway, rather than to the Galpha(q/11)-phospholipase C signaling system. This might be responsible for the different actions of LHRH in anterior pituitary and in prostate cancer.

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Section: Discussionsupporting

confidence: 91%

The Luteinizing Hormone-Releasing Hormone Receptor in Human Prostate Cancer Cells: Messenger Ribonucleic Acid Expression, Molecular Size, and Signal Transduction Pathway

Limonta¹

1999

Endocrinology

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Section: Discussionsupporting

confidence: 91%

The Luteinizing Hormone-Releasing Hormone Receptor in Human Prostate Cancer Cells: Messenger Ribonucleic Acid Expression, Molecular Size, and Signal Transduction Pathway1

et al. 1999

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Evidence has accumulated indicating that LHRH might behave as an autocrine/paracrine growth inhibitory factor in some peripheral tumors. However, LHRH receptors in tumor cells have not been fully characterized, so far. The present experiments were performed to analyze: 1) the messenger RNA expression; 2) the molecular size; and 3) the signal transduction pathway of LHRH receptors in prostate cancer. For these studies, the human androgen-dependent LNCaP and androgen-independent DU 145 prostate cancer cell lines were used. 1) By RT-PCR, a complementary DNA product, which hybridized with a 32 P-labeled oligonucleotide probe specific for the pituitary LHRH receptor complementary DNA, was found both in LNCaP and in DU 145 cells. 2) Western blot analysis, using a monoclonal antibody raised against the human pituitary LHRH receptor, revealed the presence of a protein band of approximately 64 kDa (corresponding to the molecular mass of the pituitary receptor) in both cell lines. 3) In LNCaP and DU 145 cells, pertussis toxin completely abrogated the antiproliferative action of a LHRH agonist (LHRH-A). Moreover, LHRH-A substantially antagonized the pertussis toxin-catalyzed ADP-ribosylation of a G␣ i protein. Finally, LHRH-A significantly counteracted the forskolin-induced increase of intracellular cAMP levels in both cell lines. These data demonstrate that the LHRH receptor, which is present in prostate cancer cells, independently of whether they are androgen-dependent or not, corresponds to the pituitary receptor, in terms of messenger RNA expression and protein molecular size. However, at variance with the receptor of the gonadotrophs, prostate cancer LHRH receptor seems to be coupled to the G␣ i protein-cAMP signal transduction pathway, rather than to the G␣ q/11 -phospholipase C signaling system. This might be responsible for the different actions of LHRH in anterior pituitary and in prostate cancer. (Endocrinology 140: 5250 -5256, 1999)

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“…In breast, endometrial and ovarian cancer cell lines, GnRH agonists reduce tyrosine kinase activity at the membrane level as well as the specific tyrosine autophosphorylation of the EGF receptor. These effects appear to be mediated by the activation of a phosphotyrosine phosphatase [117,119,126,127]. Other studies in human benign prostate hyperplasia (BPH-I) and in choriocarcinoma (JEG-3) cells show that GnRH analogs stimulate apoptosis through Gαi activation of stress-activated protein kinases (p38 and JNK) [115].…”

Section: Molecular Mechanisms Of the Antitumor Activity Of Gnrh Agonistsmentioning

confidence: 97%

“…In line with these observations, the possible involvement of a Gαi protein in the antitumoral activity of GnRH and of its synthetic analogs has also been reported for cancers of the female reproductive tract. In ovarian and endometrial carcinoma cells, GnRH agonists decrease the pertussis toxininduced ADP ribosylation of an immunodetected Gαi [117][118][119][120]. Surprisingly, the GnRH receptor expressed in melanoma cells does not seem to be coupled to a Gαi/cAMP system [Moretti and coworkers, unpublished observations].…”

Section: Molecular Mechanisms Of the Antitumor Activity Of Gnrh Agonistsmentioning

confidence: 99%

Gonadotropin-Releasing Hormone (GnRH) Receptors in Tumors: a New Rationale for the Therapeutical Application of GnRH Analogs in Cancer Patients?

Marelli

Moretti²,

Januszkiewicz-Caulier³

et al. 2006

CCDT

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Gonadotropin-Releasing Hormone (GnRH) is the hypothalamic decapeptide which plays a key role in the control of reproductive functions. By binding to specific receptors present on the pituitary gonadotropes, GnRH regulates gonadotropin release and, consequently, steroid hormone secretion from the gonads. When given continuously and at high doses, GnRH agonists suppress the pituitary gonadal axis through the down-regulation and desensitization of its own receptors. Based on this rationale, pituitary GnRH receptors represent the target for the successful utilization of GnRH agonists (that are more stable than the native peptide) for the treatment of hormone-dependent tumors (e.g., prostate, breast, endometrial, ovarian cancers). The observation that GnRH receptors are expressed in steroid-dependent tumors, and that their activation reduces cell proliferation and metastatic behavior of cancer cell lines, both in vitro and in vivo (when inoculated into nude mice), indicates a possible additional and more direct antitumor activity for these compounds. Interestingly, GnRH receptors have been shown to be expressed also in androgen-independent prostate carcinoma, as well as in tumors that are not classically considered hormone-related (e.g., melanoma), suggesting a clinical utility of the administration of GnRH analogs also in these tumors. More recently, GnRH agonists have been proposed as useful carriers to target cytotoxic drugs or toxins to cancer cells displaying the specific GnRH receptors. A second form of GnRH (designated GnRH-II) has been discovered in most vertebrates, including humans. GnRH-II has been suggested to act through a 'putative' cognate type II GnRH receptor, which is distributed in different tissues, both normal and tumoral. In humans, a full-length functional type II GnRH receptor has not been found. Therefore, its functions as well as its possible utility as a molecular target for a GnRH-II based therapy in oncology still has to be clarified. This review will focus on the role of GnRH receptors in the control of tumor growth, progression and dissemination. It will also be discussed whether the presence of these receptors might represent an additional rationale for the clinical utility of GnRH analogs as anticancer drugs.

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Signal Transduction of GnRH Receptor in the Reproductive.

Cited by 21 publications

References 112 publications

The Luteinizing Hormone-Releasing Hormone Receptor in Human Prostate Cancer Cells: Messenger Ribonucleic Acid Expression, Molecular Size, and Signal Transduction Pathway

The Luteinizing Hormone-Releasing Hormone Receptor in Human Prostate Cancer Cells: Messenger Ribonucleic Acid Expression, Molecular Size, and Signal Transduction Pathway

The Luteinizing Hormone-Releasing Hormone Receptor in Human Prostate Cancer Cells: Messenger Ribonucleic Acid Expression, Molecular Size, and Signal Transduction Pathway1

Gonadotropin-Releasing Hormone (GnRH) Receptors in Tumors: a New Rationale for the Therapeutical Application of GnRH Analogs in Cancer Patients?

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