Luteinizing hormone-releasing hormone agonist triptorelin antagonizes signal transduction and mitogenic activity of epidermal growth factor in human ovarian and endometrial cancer cell lines

Emons, Günter; Müller, V.; Ortmann, O.; Grossmann, Gereon; Trautner, Ursula; Stuckrad, Bettina V.; Schulz, K.-D.

doi:10.3892/ijo.9.6.1129

Cited by 44 publications

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“…Although we were able to demonstrate clearly the activation of PLC, PKC and adenylyl cyclase in these tumor cells by pharmacological stimuli, the GnRH agonist triptorelin, in concentrations that were inhibitory to proliferation, had no effects on the activity of these signaling systems (76). We found, however, that the mitogenic effect of growth factors in these cell lines could be counteracted by triptorelin, indicating an interaction with the mitogenic signal transduction pathway (76). Comparable data were obtained by Moretti et al (77) in the human prostatic cancer cell lines LNCaP and DU 145.…”

Section: Molecular Mechanisms Mediating the Direct Antitumor Effects mentioning

confidence: 63%

“…We demonstrated that EGF-induced activation of MAPK, an enzyme further downstream in the growth factor signaling cascade (87), was virtually completely blocked in ovarian and endometrial cancer cells treated with the GnRH agonist triptorelin (76). By quantitative RT-PCR and western blotting, we showed that the EGF-induced expression of the immediate early gene c-fos, a mechanism still further downstream in mitogenic signaling, was completely abrogated in breast, ovarian and endometrial cancer cells by treatment with the GnRH agonist triptorelin or with the GnRH antagonist cetrorelix (88) (Fig.…”

Section: Molecular Mechanisms Mediating the Direct Antitumor Effects mentioning

confidence: 92%

“…It is likely that the antiproliferative effects of GnRH analogs might be directly mediated through inhibition of growth factor signaling on its first step, the auto-phosphorylation of tyrosine residues of growth factor receptors. Some indirect evidence that GnRH activates a PTP was found by Imai et al (83) and by Emons et al (76), showing that GnRH reduces the net tyrosine phosphorylation of membrane proteins. Direct evidence for the G-protein ai-mediated activation of a PTP and a reduction in EGF receptor tyrosine phosphorylation by GnRH had not been obtained to date.…”

Section: Molecular Mechanisms Mediating the Direct Antitumor Effects mentioning

confidence: 96%

“…These findings were in accord with reports that GnRH analogs reduced expression of growth factor receptors and their mRNA (61,77,78) or growth-factor-induced tyrosine kinase activity, or both (76, 77, 79 -84). Growth-factor-induced tyrosine phosphorylation is probably counteracted by GnRH analogs through activation of a phosphotyrosine phosphatase (PTP) (76,77,80,81,83,84), which is probably coupled to the GnRH receptor through a G-protein ai in human reproductive tract tumors (85). Using an antibody against tyrosine phosphate, we were able to show that the GnRH agonist triptorelin and the antagonist cetrorelix reduce epidermal growth factor (EGF)-induced tyrosine auto-phosphorylation of EGF receptors to 60 -80% of that in controls.…”

Section: Molecular Mechanisms Mediating the Direct Antitumor Effects mentioning

confidence: 99%

“…In addition, triptorelin activates c-Jun N-terminal kinase (JNK), which is known to activate AP-1 (102). In earlier investigations, we have shown that triptorelin does not activate PLC and PKC in endometrial and ovarian cancer cells (76). In addition, it has been demonstrated that triptorelin inhibits growth-factor-induced MAPK activity (76).…”

Section: Additional Signaling Mechanismsmentioning

confidence: 99%

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Biology of the gonadotropin-releasing hormone system in gynecological cancers

Gründker

Gunthert

Westphalen

et al. 2002

European Journal of Endocrinology

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155

139

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The expression of GnRH 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 breast, ovary and endometrium. Dose-dependent antiproliferative effects of GnRH agonists in cell lines derived from these cancers have been observed by various investigators. GnRH antagonists also have marked antiproliferative activity in most breast, ovarian and endometrial cancer cell lines tested, indicating that the dichotomy of GnRH agonists and antagonists might not apply to the GnRH system in cancer cells. 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 cancer cells. Rather, the GnRH receptor 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 nuclear factor kB and protects the cancer cells from apoptosis. Furthermore, GnRH induces activation of the c-Jun N-terminal kinase/activator protein-1 (AP-1) pathway independent of the known AP-1 activators, protein kinase or mitogen activated protein kinase.

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Section: Molecular Mechanisms Mediating the Direct Antitumor Effects mentioning

confidence: 63%

Section: Molecular Mechanisms Mediating the Direct Antitumor Effects mentioning

confidence: 92%

Section: Molecular Mechanisms Mediating the Direct Antitumor Effects mentioning

confidence: 96%

Section: Molecular Mechanisms Mediating the Direct Antitumor Effects mentioning

confidence: 99%

Section: Additional Signaling Mechanismsmentioning

confidence: 99%

See 3 more Smart Citations

Biology of the gonadotropin-releasing hormone system in gynecological cancers

Gründker

Gunthert

Westphalen

et al. 2002

European Journal of Endocrinology

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155

139

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Inhibitory effects of a luteinizing hormone‐releasing hormone agonist on basal and epidermal growth factor‐induced cell proliferation and metastasis‐associated properties in human epidermoid carcinoma a431 cells

Huang

Hwang²,

Lee

et al. 2002

Intl Journal of Cancer

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The life threatening characteristics of cancers lie in the uncontrolled cell mitogenic activity and the acquiring of metastatic capability. Therefore, the strategies for cancer therapy are aimed at controlling the cancer cell growth and/or inhibiting the cancer cell invasion/metastasis. Early reports contended that protein tyrosine kinase (PTK) regulatory mechanisms are clearly implicated in the growth of neoplastic cells, and inactivating specific PTKs could retard the growth of tumors. 1-3 Among the PTKs investigated, epidermal growth factor receptor (EGFR) tyrosine kinase has attracted much attention with regard to its role in transducing signal for promoting cell growth. Autophosphorylation of EGFR appears to be a potential target for cancer therapy because that would engender a blockade of the EGFR-mediated signaling. 3 In light of this, it is imperative to explore whether luteinizing hormone-releasing hormone (LHRH) analogues that possess antiproliferative activity could have any direct effects on the autophosphorylation of EGFR and its intrinsic tyrosine kinase activity.More than 3 decades have passed since the isolation and characterization of the hypothalamic LHRH, which controls the anterior pituitary secretion of luteinizing hormone and follicle stimulating hormone. 4 Accumulated data have indicated that LHRH might also present in extra-hypothalamic tissues, such as ovary, testis, kidney and placenta. 5 Currently, more than 3,000 analogues of LHRH have been synthesized. 6 Agonists of LHRH have important clinical applications in gynecology and oncology. 6 Potent antagonists of LHRH, such as Cetrorelix, are also available for clinical use. 6 The actions of LHRH and its analogues are mediated by high-affinity receptors for LHRH found on pituitary gonadotrophs and various tumors. 6 The presence of high affinity binding sites for LHRH and the expression of mRNA for LHRH receptors have been shown in human prostatic, mammary, ovarian and endometrial cancers. These LHRH receptors on tumor cells can mediate direct effects of LHRH agonists and antagonists. Inhibitory effects of LHRH agonists and antagonists on prostatic, mammary, ovarian and endometrial cancer cells have been demonstrated in vitro. 6 -11 Thus, a potent agonist ]LHRH and LHRH antagonist Cetrorelix synthesized in the laboratory of one of us (A.V.S.) 6 was shown to inhibit the growth of human ovarian endometrial and mammary cancer cells 9 and LHRH agonists Zoladex and Buserelin suppressed the proliferation of human prostate cancer lines. 7,10 The effects of LHRH-analogues on mitogenic signal transduction in cancer cells were also the subjects of extenAbbreviations: DMSO, dimethyl sulphoxide; EDTA, ethylenediamine tetraacetic acid; EGF, epidermal growth factor; EGFR, epidermal growth factor receptor; ICE, interleukin-1␤ converting enzyme; LHRH, luteinizing hormone-releasing hormone; MMP, matrix metalloproteinase; PARP, poly(ADP-ribose) polymerase; PTK, protein tyrosine kinase; PTP, protein tyrosine phosphatase; SDS-PAGE, sodium dodecyl sulphate-p...

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GnRH analogs reduce invasiveness of human breast cancer cells

Alten

Fister

Schulz

et al. 2006

Breast Cancer Res Treat

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These data represent the first report that the activation of tumor GnRH receptors reduces the metastatic potential of breast cancer cells. The crosstalk between metastatic breast cancer cells and bone is critical to the development and progression of bone metastases. Disruption of this interaction will allow us to design mechanism-based effective and specific therapeutic interventions for bone metastases.

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Luteinizing hormone-releasing hormone agonist triptorelin antagonizes signal transduction and mitogenic activity of epidermal growth factor in human ovarian and endometrial cancer cell lines

Cited by 44 publications

References 0 publications

Biology of the gonadotropin-releasing hormone system in gynecological cancers

Biology of the gonadotropin-releasing hormone system in gynecological cancers

Inhibitory effects of a luteinizing hormone‐releasing hormone agonist on basal and epidermal growth factor‐induced cell proliferation and metastasis‐associated properties in human epidermoid carcinoma a431 cells

GnRH analogs reduce invasiveness of human breast cancer cells

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