Follicle-stimulating hormone promotes the growth of human epithelial ovarian cancer cells through the protein kinase C-mediated system

We have previously described that follicle-stimulating hormone (FSH) stimulated the growth of human epithelial ovarian cancer tissues and cells. In order to determine the signaling pathway on FSH action in ovarian cancer, we used an epithelial ovarian cancer cell line (HRA line) which constitutively FSH receptors (FSHRs). FSH significantly increased cell proliferation (230.1 +/- 20.5%, P < 0.05) and H-3-thymidine uptake (443.5 +/- 35.1%, P < 0.01). 1-(5-Isoquinolinesulfonyl)-2-methyipiperazine (H7, 1 5 nM), staurosponine (STR, 5 nM) and calphostin C (5 nM), specific protein kinase C (PKC) inhibitors, significantly suppressed the FSH-stimulated cell growth (120.2-140.2%, P < 0.05) and H-3-thymidine uptake (140.5-173.9%, P < 0.05), whereas N-(2-guanidinoethyl)-5-isoquinoline-sulfon-amide (HA1004, 15 nM), which is a derivant of H7 and inhibits most of protein kinases except PKC, showed no effect on the FSH-stimulated cell growth and H-3-thymidine uptake. A pretreatment with 12-0-tetradecanoylphorbol-13 acetate (TPA, 100 ng/ml) or STR (20 nM) significantly suppressed the subsequent FSH-stimulated cell growth (TPA; 152.3 +/- 10.3%, STR; 160.4 +/- 15.9%, P < 0.05) and H-3-thymidine uptake (TPA; 250.4 +/- 18.3%, STR; 208.7 +/- 15.9%, P < 0.05). STR abolished the suppression of TPA preincubation on the subsequent FSH-stimulated cell growth and H-thymidine uptake. HRA cells constitutively expressed PKC alpha but not PKC beta nor PKC gamma. The levels of either expression of PKC alpha protein and mRNA were significantly amplified by FSH. These data suggest that stimulation of PKC alpha transcription is involved in the FSH stimulated cell growth and DNA synthesis in epithelial ovarian cancer cells. (C) 2001 Elsevier Science Ireland Ltd. All rights reserved.