Luteinizing hormone-releasing hormone as an autocrine growth factor in ES-2 ovarian cancer cell line

Agonistic and antagonistic analogs of luteinizing hormone-releasing hormone (LHRH) inhibit the growth of various cancers in vivo. This effect is mainly exerted through the suppression of the pituitary-gonadal axis and the creation of a state of sex steroid deprivation. In addition, much evidence has been accumulated in the past few years that LHRH analogs can also have direct effects on tumor growth mediated by specific LHRH receptors (-R) on tumor cells. Although an involvement of LHRH in the proliferation of some cancer cells has been postulated, it is still not clear at present whether LHRH produced locally has a stimulatory or inhibitory effect. In the present study we investigated whether LHRH can function as an autocrine growth factor in ovarian cancer. ES-2 human ovarian cancer cell line expresses mRNA for LHRH, which is apparently translated into peptide LHRH and then secreted by the cells, as demonstrated for the first time by the detection of LHRH-like immunoreactivity in conditioned media from the cells cultured in vitro. ES-2 cells also express mRNA for LHRH receptors. [D-Trp6]LHRH agonist at 10 ng/ml stimulates the proliferation of ES-2 in vitro after 48 h, but is inhibitory after 72 h and at concentrations of 1000 ng/ml. LHRH antagonist Cetrorelix inhibits growth of ES-2 cell line only at 1000 ng/ml. The incubation of ES-2 ovarian cancer cells in vitro with an LHRH antibody inhibited cell proliferation in a time and concentration-dependent manner. Collectively, our results suggest that LHRH may function as an autocrine growth factor in ovarian cancer.