A. Bagnato et al., AUTOCRINE ACTIONS OF ENDOTHELIN-1 AS A GROWTH-FACTOR IN HUMAN OVARIAN-CARCINOMA CELLS, Clinical cancer research, 1(9), 1995, pp. 1059-1066
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.