Targeted destruction of androgen-sensitive and -insensitive prostate cancer cells and xenografts through luteinizing hormone receptors

Gonadotrophin-releasing hormone receptors (GnRH-Rs) are found in cancers of reproductive tissues, including those of the prostate, and gonadotrophin-releasing hormone (GnRH) can inhibit growth of cell lines derived from such cancers. Although pituitary and extra-pituitary GnRH-R transcripts appear identical, their functional characteristics may differ. Most extra-pituitary GnRH-Rs have low affinity for GnRH analogues and may not activate phospholipase C or discriminate between agonists and antagonists in the same way as do pituitary GnRH-Rs. Here we have assessed whether GnRH-Rs expressed exogenously in prostate cancer cells differ functionally from those of gonadotrophs. We found no evidence for endogenous GnRH-Rs in PC3 cells, but after infection with adenovirus expressing the GnRH-R (Ad GnRH-R) at 10 plaque forming units (p.f.u.)/cell or greater, at least 80% of the cells expressed GnRH-Rs. These sites had high affinity (K(d )for [(125)I]Buserelin 1.1+/-0.4 nM) and specificity (rank order of potency: Buserelin> GnRH>>chicken (c) GnRH-II), and mediated stimulation of [(3)H]inositol phosphate (IP) accumulation. Increasing viral titre from 3 to 300 p.f.u./cell increased receptor number (2000 to 275 000 sites/cell respectively) and [(3)H]IP responses. GnRH also caused a biphasic increase in the cytoplasmic Ca(2+) concentration in Ad GnRH-R-infected cells but not in control cells. Mobilization of Ca(2+) from intracellular stores contributed to the spike phase of this response whereas the plateau phase was dependent upon Ca(2+) entry across the plasma membrane. This effect on Ca(2+) and stimulation of [(3)H]IP accumulation were both blocked by the GnRH-R antagonist, Cetrorelix. In addition, GnRH reduced cell number (as measured in MTT activity assays) and DNA synthesis (as measured by [(3)H]thymidine incorporation) in Ad GnRH-R-infected cells (but not in control cells). This effect was mimicked by agonist analogues and inhibited by two antagonists. Thus, when exogenous GnRH-Rs are expressed at a density comparable to that in gonadotrophs, they are functionally indistinguishable from the endogenous GnRH-Rs in gonadotrophs. Moreover, expression of high affinity GnRH-Rs can facilitate a direct anti-proliferative effect of GnRH agonists on prostate cancer cells.

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Inhibitory activity of luteinizing hormone-releasing hormone on tumor growth and progression.

Endocrine Related Cancer ◽

10.1677/erc.0.0100161 ◽

2003 ◽

pp. 161-167 ◽

Cited By ~ 23

Author(s):

R M Moretti ◽

M Monagnani Marelli ◽

J C van Groeninghen ◽

M Motta ◽

P Limonta

Keyword(s):

Prostate Cancer ◽

Cell Proliferation ◽

Luteinizing Hormone ◽

Cancer Cells ◽

Reproductive System ◽

Melanoma Cells ◽

Lhrh Agonist ◽

Prostate Cancer Cells ◽

Luteinizing Hormone Releasing Hormone ◽

Metastatic Behavior

Luteinizing hormone-releasing hormone (LHRH) is the key hormone in the control of reproductive functions. In recent years, it has become evident that LHRH might act as a growth modulatory factor in tumors of the reproductive system. We have shown that in prostate cancer cells LHRH is expressed, together with its receptors, to negatively regulate cell proliferation. In these cells, LHRH acts as an antimitogenic factor through the activation of the Gi-cAMP intracellular signaling pathway. More recently, we investigated whether an LHRH-based autocrine system might also be expressed in tumors that are not classically related to the reproductive tract, such as melanoma. Malignant melanoma is known to be characterized not only by a high proliferation rate, but also by an aggressive metastatic behavior. We have demonstrated that both LHRH and LHRH receptors are expressed in human melanoma cells (BLM and Me15392). Activation of LHRH receptors by means of a potent LHRH agonist (Zoladex) significantly inhibited cell proliferation. The LHRH agonist also reduced the ability of melanoma cells to invade a reconstituted basement membrane (Matrigel) and to migrate in response to a chemotactic stimulus. These data indicate that: (a) in prostate cancer cells the LHRH receptor is coupled to a Gi-cAMP signal transduction pathway; (b) LHRH and LHRH receptors are also expressed in tumors that are not classically related to the reproductive system, such as melanoma; in melanoma cells, LHRH might act as an inhibitory factor on both cell proliferation and metastatic behavior. It is suggested that, in melanoma, LHRH receptors might represent a diagnostic marker and a possible molecular target for new therapeutic approaches for this pathology.

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