Cell growth of ovarian cancer cells is stimulated by xenoestrogens through an estrogen-dependent pathway, but their stimulation of cell growth appears not to be involved in the activation of the mitogen-activated protein kinases ERK-1 and p38.
Although endocrine disrupting chemicals (EDCs) may interfere with the endocrine system(s) of our body and have estrogenicity or androgenicity, the exact mechanism(s) underlying their detrimental effects is not clearly understood. Thus, in this study, we evaluated the effects of EDCs on proliferation and regulation of transcription of estrogen receptor (ER)-positive BG-1 ovarian cancer cells, and their possible mechanisms were further examined. Treatment with bisphenol A (BPA), nonylphenol (NP), octylphenol (OP) and methoxychlor (MXC) for 24 h resulted in an increase of cell proliferation. Treatment with BPA, NP, OP and MXC increased the estrogen response element (ERE) activity. The increase of cell proliferation and activation of ERE were reversed in the presence of an estrogen receptor antagonist, ICI 182780. These results suggest that ER is involved in EDC-mediated pathway in ovarian cancer cells. Based on this, we further investigated the involvement of EDCs in activation of mitogen-activated protein kinase (MAPK) in relation to cell growth. BPA rapidly induced activation of extracellular signal-regulated kinase (ERK) 1/2 and p38 MAPK at 15 min, but the effect of BPA (10 microM) on stimulation of cell growth was not blocked by pretreatment with inhibitors of MEK (PD98059) or p38 (SB203580) in a dose-dependent manner. Taken together, EDC-induced proliferation is mediated by a genomic effect through ERs and ERE, but EDC-activated MAPK is unlikely to be involved in EDC-induced cell growth in estrogen-responsive ovarian cancer cells.
Department of Obstetrics and Gynecology, British Columbia Women's Hospital, Child and Family Research Institute, University of British Columbia, Vancouver, British Columbia, Canada.
Se-Hyung
SH
Park
Ki-Yon
KY
Kim
Beum-Soo
BS
An
Jung-Hye
JH
Choi
Eui-Bae
EB
Jeung
Peter C K
PC
Leung
Kyung-Chul
KC
Choi
D048708:Cell Growth Processes / Q000187:drug effects* / Q000235:genetics; D052244:Endocrine Disruptors / Q000494:pharmacology; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004967:Estrogens / Q000494:pharmacology*; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000473:pathology*; D011725:Pyridines / Q000494:pharmacology; D011960:Receptors, Estrogen / Q000235:genetics / Q000502:physiology; D020218:Response Elements / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D014407:Tumor Cells, Cultured; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*
D052244:Endocrine Disruptors; D004791:Enzyme Inhibitors; D004967:Estrogens; D005419:Flavonoids; D007093:Imidazoles; D011725:Pyridines; D011960:Receptors, Estrogen; D048052:Mitogen-Activated Protein Kinase 3; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one