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 (3)H-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 (3)H-thymidine uptake (140.5-173.9%, P < 0.05), whereas N-(2-guanidinoethyl)-5-isoquinoline-sulfon-amide (HA1004, l5 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 (3)H-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 (3)H-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 (3)H-thymidine uptake. HRA cells constitutively expressed PKCalpha but not PKCbeta nor PKCgamma. The levels of either expression of PKCalpha protein and mRNA were significantly amplified by FSH. These data suggest that stimulation of PKCalpha transcription is involved in the FSH-stimulated cell growth and DNA synthesis in epithelial ovarian cancer cells.
Ohtani
K
K
Department of Obstetrics and Gynecology, Nihon university School of Medicine, 30-1, Oyaguchi-kamimachi, Itabashi-ku, 173, Tokyo, Japan.
Sakamoto
H
H
Kikuchi
A
A
Nakayama
Y
Y
Idei
T
T
Igarashi
N
N
Matukawa
T
T
Satoh
K
K
D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology*; D006801:Humans; D007527:Isoenzymes / Q000502:physiology; D010051:Ovarian Neoplasms / Q000473:pathology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000502:physiology*; D019311:Staurosporine / Q000494:pharmacology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013936:Thymidine
D004791:Enzyme Inhibitors; D007527:Isoenzymes; D005640:Follicle Stimulating Hormone; D011493:Protein Kinase C; D019311:Staurosporine; D013755:Tetradecanoylphorbol Acetate; D013936:Thymidine