Evidence for coupling of phosphotyrosine phosphatase to gonadotropin-releasing hormone receptor in ovarian carcinoma membrane

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

doi:10.1002/(sici)1097-0142(19960101)77:1<132::aid-cncr22>3.0.co;2-5

Cited by 60 publications

(16 citation statements)

References 31 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…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%

See 1 more Smart Citation

Biology of the gonadotropin-releasing hormone system in gynecological cancers

Gründker

Gunthert

Westphalen

et al. 2002

European Journal of Endocrinology

155

139

View full text Add to dashboard Cite

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.

show abstract

Section: Molecular Mechanisms Mediating the Direct Antitumor Effects mentioning

confidence: 96%

Section: Molecular Mechanisms Mediating the Direct Antitumor Effects mentioning

confidence: 99%

Biology of the gonadotropin-releasing hormone system in gynecological cancers

Gründker

Gunthert

Westphalen

et al. 2002

European Journal of Endocrinology

155

139

View full text Add to dashboard Cite

show abstract

“…After binding of its ligand, the GnRH receptor in cancers couples to G protein αi and activates a phosphotyrosine phosphatase (Lee et al 1991, Furui et al 1995, Imai et al 1996a,b, Emons et al 1996a, Gründker et al 2001a). This phosphotyrosine phosphatase dephosphorylates epidermal growth factor (EGF) receptors (Gründker et al 2001a).…”

Section: Signal Transduction Of the Gnrh System In Human Breast Ovarmentioning

confidence: 99%

GnRH antagonists in the treatment of gynecological and breast cancers.

Emons

Gründker²,

Günthert³

et al. 2003

Endocrine-Related Cancer

133

View full text Add to dashboard Cite

Approximately 80% of human ovarian and endometrial cancers and 50% of breast cancers express GnRH and its receptor as part of an autocrine regulatory system. After binding of its ligand the tumor GnRH receptor couples to G-protein αi and activates a variety of intracellular signaling mechanisms.(1) Through activation of a protein tyrosine phosphatase, autophosphorylation of growth factor receptors is reverted leading to an inhibition of mitogenic signaling and reduced cell proliferation. (2) Through activation of nuclear factor kappa B antiapoptotic mechanisms are induced protecting tumor cells from apoptosis induced, for example, by doxorubicin. (3) Through activation of the Jun kinase pathway AP-1 is induced, leading to cell cycle arrest in the G 0 /G 1 phase. It seems reasonable to speculate that this system enables the tumor cell to reduce proliferation and to activate repair mechanisms while being protected simultaneously from apoptosis. Interestingly, GnRH antagonists show the same activity in this system as agonists, indicating that the dichotomy GnRH agonist-GnRH antagonist defined in the pituitary gonadotrope is not valid for the tumor GnRH system. Recently, a second type of GnRH receptor, specific for GnRH-II, has been identified in ovarian and endometrial cancers, which transmits significantly stronger antiproliferative effects than the GnRH-I receptor. GnRH antagonists have agonistic effects on this type II receptor. In animal models of human cancers, GnRH antagonists had stronger antitumor effects than GnRH agonists. Therefore, we performed a phase II clinical trial with the GnRH antagonist, cetrorelix (10 mg/day), in patients with ovarian or mullerian carcinoma refractory to platinum chemotherapy. Of 17 evaluable patients treated with cetrorelix, 3 obtained a partial remission (18%) which lasted for 2 to 6 months. Furthermore, 6 patients experienced disease stabilization (35%) for up to 1 year. In this very refractory patient population (median number of prior chemotherapies = 3) these results are quite remarkable when compared with palliative chemotherapy. In addition, cytotoxic GnRH analogs have been developed, where for example doxorubicin was covalently coupled to GnRH analogs. These compounds have superior antitumor effects in cancers expressing GnRH receptors as compared with native doxorubicin and allow for a targeted cytotoxic chemotherapy of gynecologic and breast cancers.

show abstract

“…analogs reduce expression of EGF receptors and their mRNA 15,53 and/or EGF-induced tyrosine kinase activity. 13,15,41,54 EGF-induced tyrosine phosphotyrosine is probably counteracted by LH-RH analogs through activation of a phosphotyrosine phosphatase. 12 Several lines of evidence suggest that the induction of cellular protein tyrosine phosphatase (PTP) activity correlates with growth inhibition of several cancer cells.…”

Section: Effects Of [D-trp 6 ]Lhrh On Basal and Egf-induced Metastasimentioning

confidence: 99%

“…The inhibitory effects of LHRH analogues on cell growth and cellular protein phosphorylation was also observed in MiaPaCa-2 and ovarian tumor cells. 11,16,54 The similarity in analogue efficacy between repression of tyrosine phosphorylation and inhibition of cell proliferation suggests that net tyrosine phosphorylation of 1 (or more) signaling molecules may well be an important determining factor for growth control. Interestingly, our current and previous studies 11,16 LHRH.…”

Section: Effects Of [D-trp 6 ]Lhrh On Basal and Egf-induced Metastasimentioning

confidence: 99%

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

View full text Add to dashboard Cite

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...

show abstract

Evidence for coupling of phosphotyrosine phosphatase to gonadotropin-releasing hormone receptor in ovarian carcinoma membrane

Cited by 60 publications

References 31 publications

Biology of the gonadotropin-releasing hormone system in gynecological cancers

Biology of the gonadotropin-releasing hormone system in gynecological cancers

GnRH antagonists in the treatment of gynecological and breast 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

Contact Info

Product

Resources

About