Gonadotropins activate proteolysis and increase invasion through protein kinase A and phosphatidylinositol 3-kinase pathways in human epithelial ovarian cancer cells.
Despite evidence that gonadotropins may facilitate peritoneal metastasis of ovarian cancer by increasing cell adhesion, the action and molecular mechanism of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in ovarian cancer invasion is not well characterized. In the present study, we investigated the effects of FSH and LH on the invasive activity and the expression of metastasis-related proteinases in human epithelial ovarian cancer by Western blot, zymography, reverse transcription-PCR (RT-PCR), ELISA, and Boyden chamber assay. Treatment with FSH or LH (10, 100, or 1,000 ng/mL) significantly increased the invasion of ovarian cancer cell lines, including BG-1, CaOV-3, and SKOV-3 cells but not OVCAR-3 cells. In addition, treatment of SKOV-3 cells with FSH or LH (100 or 1,000 ng/mL) enhanced the expression and activation of matrix metalloproteinases (MMP-2 and MMP-9) as shown by RT-PCR, gelatin zymography, and ELISA. Pretreatment with [(2R)-2-(hydroxamido-carbonylmethyl)-4-methylpentanoyl]-l-tryptophan methylamide (10 micromol/L), a total MMP inhibitor, and 3-(4-phenoxyphenylsulfonyl)-propylthiirane (20 micromol/L), a specific gelatinase inhibitor, neutralized the proinvasive effect of gonadotropins in SKOV-3 cells. In addition, the secretion of tissue inhibitor of metalloproteinases (TIMP-1 and TIMP-2) and plasminogen activator inhibitor-1 was significantly decreased by FSH and LH (100 or 1,000 ng/mL). We further showed that gonadotropins induced an increase in SKOV-3 invasiveness via the activation of protein kinase A (PKA) and phosphatidylinositol 3-kinase (PI3K) signaling pathways. Taken together, these results suggest that gonadotropins may contribute to ovarian cancer metastasis via activation of proteolysis and increase in invasion through the PKA and PI3K pathways.
Department of Obstetrics and Gynecology, British Columbia Children's and Women's Hospital, Child and Family Research Institute, University of British Columbia, 4490 Oak Street, Vancouver, British Columbia, Canada V6H 3V5.
Jung-Hye
JH
Choi
Kyung-Chul
KC
Choi
Nelly
N
Auersperg
Peter C K
PC
Leung
D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000201:enzymology; D005260:Female; D005640:Follicle Stimulating Hormone / Q000494:pharmacology*; D006801:Humans; D007546:Isoquinolines / Q000494:pharmacology; D007986:Luteinizing Hormone / Q000494:pharmacology*; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009361:Neoplasm Invasiveness; D010051:Ovarian Neoplasms / Q000201:enzymology* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017395:Plasminogen Activator Inhibitor 1 / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D011994:Recombinant Proteins / Q000494:pharmacology; D013449:Sulfonamides / Q000494:pharmacology; D014568:Urokinase-Type Plasminogen Activator / Q000378:metabolism
D002867:Chromones; D017868:Cyclic AMP-Dependent Protein Kinases; D004791:Enzyme Inhibitors; D005640:Follicle Stimulating Hormone; D007546:Isoquinolines; D007986:Luteinizing Hormone; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D009025:Morpholines; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; D011994:Recombinant Proteins; D013449:Sulfonamides; D014568:Urokinase-Type Plasminogen Activator; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide