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 actions on calcium signaling and growth responses were analyzed in human ovarian carcinoma cells. Immuno-reactive ET-1 was released from three of four ovarian tumor cell lines as a function of time in amounts ranging from 56 to 74 fmol/10(6) cells. Reverse-phase HPLC and radioimmuno-assay of conditioned media from tumor cells revealed a single peak coeluting with authentic ET-1. Radioligand binding studies showed that the ET-1-producing cell lines also expressed high-affinity ETA receptors (Kd < 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-dependent increases in cytoplasmic Ca2+ concentration. ET-1 also stimulated thymidine incorporation in the three cell lines that expressed ET receptors. In OVCA 433 cells, BQ 123 inhibited the stimulatory actions of ET-1 on thymidine incorporation and cell proliferation, and substantially reduced the basal growth rate of unstimulated ovarian tumor cells. These results demonstrate that ET-1 is produced in ovarian cancer cells and acts as an autocrine growth factor on ETA receptors to stimulate calcium signaling and proliferative responses. Such findings suggest that ET-1 participates in the progression of neoplastic growth in certain ovarian tumors.
Bagnato
A
A
Laboratory of Molecular Pathology and Ultrastructure, Regina Elena Cancer Institute, Via delle Messi D'Oro 156-158, 00158 Rome, Italy.
Tecce
R
R
Moretti
C
C
Di Castro
V
V
Spergel
D
D
Catt
K J
KJ
D002118:Calcium / Q000378:metabolism; D002455:Cell Division; D019332:Endothelin-1 / Q000378:metabolism / Q000502:physiology*; D005260:Female; D006801:Humans; D009363:Neoplasm Proteins / Q000378:metabolism / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000378:metabolism* / Q000473:pathology; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000378:metabolism; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured
D019332:Endothelin-1; D009363:Neoplasm Proteins; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D002118:Calcium; D013936:Thymidine