The Role of Gonadotropin-Releasing Hormone in Cancer Cell Proliferation and Metastasis

Abstract

In several human malignant tumors of the urogenital tract, including cancers of the endometrium, ovary, urinary bladder, and prostate, it has been possible to identify expression of gonadotropin-releasing hormone (GnRH) and its receptor as part of an autocrine system, which regulates cell proliferation. The expression of GnRH receptor has also been identified in breast cancers and non-reproductive cancers such as pancreatic cancers and glioblastoma. Various investigators have observed dose- and time-dependent growth inhibitory effects of GnRH agonists in cell lines derived from these cancers. GnRH antagonists have also shown marked growth inhibitory effects on most cancer cell lines. This indicates that in the GnRH system in cancer cells, there may not be a dichotomy between GnRH agonists and antagonists. The well-known signaling mechanisms of the GnRH receptor, which are present in pituitary gonadotrophs, are not involved in forwarding the antiproliferative effects of GnRH analogs in cancer cells. Instead, the GnRH receptor activates a phosphotyrosine phosphatase (PTP) and counteracts with the mitogenic signal transduction of growth factor receptors, which results in a reduction of cancer cell proliferation. The PTP activation, which is induced by GnRH, also inhibits G-protein-coupled estrogen receptor 1 (GPER), which is a membrane-bound receptor for estrogens. GPER plays an important role in breast cancers, which do not express the estrogen receptor α (ERα). In metastatic breast, ovarian, and endometrial cancer cells, GnRH reduces cell invasion in vitro, metastasis in vivo, and the increased expression of S100A4 and CYR61. All of these factors play important roles in epithelial–mesenchymal transition. This review will summarize the present state of knowledge about the GnRH receptor and its signaling in human cancers.

Genome-wide Analysis of Common Copy Number Variation and Epithelial Ovarian Cancer Risk

“…Published analyses of TCGA data identified 8p21.2 as one of the 40 most common focal deletions in ovarian cancer genomes and the deletions correlated with GNRH1 expression (48). This indication of 8p21 as a tumor suppressor gene locus coincides with strong evidence that the extrapituitary, autocrine function of GnRH, involved in follicular development in the ovary (49), counteracts growth factor receptor signaling and exerts antiproliferative and antimotility effects in ovarian and other tumors (50). Our group previously observed SNPs within GNRH1 that exhibited gene-level associations with increased HGSOC risk (51); we now report the first indication of an association between HGSOC risk and germline CNV at this region.…”

Cardiovascular risk with androgen deprivation therapy

“…The rationale for ADT in PCa stems from Huggins and Hodges' observation that T production influences PCa growth . Although bilateral surgical orchiectomy remains a common form of ADT in some parts of the world, medical options including GnRH agonists and antagonists are commonly used to reduce serum T levels on par with levels resulting from bilateral orchiectomy …”

“…1 Although bilateral surgical orchiectomy remains a common form of ADT in some parts of the world, medical options including GnRH agonists and antagonists are commonly used to reduce serum T levels on par with levels resulting from bilateral orchiectomy. 10 After a review of available evidence (which showed small but statistically significant increased risks of diabetes and/or CV events in patients taking GnRH agonists), the FDA mandated in October 2010 that labels of GnRH agonists include safety information regarding these risks. 6 "Although the risk for diabetes and CV diseases appears to be low in men receiving GnRH agonists for prostate cancer," said the FDA, "it is important for healthcare professionals to evaluate patients for risk factors for these diseases.…”

Targeting of peptide‐binding receptors on cancer cells with peptide‐drug conjugates

“…[ 46 ] Targeting of the GnRH‐R with activating peptide or small molecule agonists is already applied in cancer therapy. [ 47 ] For the generation of drug conjugates, the modified GnRH analogs [ d ‐Lys 6 ]‐GnRH‐I and [Lys 4 ]‐GnRH‐III are most frequently used. [ 48,49 ]…”