AUTOCRINE ACTIONS OF ENDOTHELIN-1 AS A GROWTH-FACTOR IN HUMAN OVARIAN-CARCINOMA CELLS

The production of endothelin 1 (ET-1) and its receptor-mediated action s on calcium signaling and growth responses were analyzed in human ova rian carcinoma cells. Immunoreactive ET-1 was released from three of f our ovarian tumor cell lines as a function of time in amounts ranging from 56 to 74 fmol/10(6) cells. Reverse-phase HPLC and radioimmunoassa y of conditioned media from tumor cells revealed a single peak coeluti ng with authentic ET-1. Radioligand binding studies showed that the ET -1-producing cell lines also expressed high-affinity ET(A) receptors ( K-d < 0.1 nM) that ranged in abundance from 2,600 to 43,600 sites/cell . In fura-2-loaded ovarian carcinoma cells, ET-1 induced dose-dependen t increases in cytoplasmic Ca2+ concentration. ET-1 also stimulated th ymidine incorporation in the three cell lines that expressed ET recept ors. In OVCA 433 cells, BQ 123 inhibited the stimulatory actions of ET -1 on thymidine incorporation and cell proliferation, and substantiall y reduced the basal growth rate of unstimulated ovarian tumor cells, T hese results demonstrate that ET-1 is produced in ovarian cancer cells and acts as an autocrine growth factor on ET, receptors to stimulate calcium signaling and proliferative responses, Such findings suggest t hat ET-1 participates in the progression of neoplastic growth in certa in ovarian tumors.