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

Abstract

Abstract. 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 μM) 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. Key words: Endocrine disrupting chemical, Estrogen receptor, Estrogen response element, Extracellular signalregulated kinase, Mitogen-activated protein kinase (J. Reprod. Dev. 55: [23][24][25][26][27][28][29] 2009) varian carcinoma is one of the most frequent gynaecologic cancers, following breast, lung and colorectal cancer [1]. Although the biological causes of ovarian cancer remain unknown, hormonal factors such as estrogen or gonadotropins have been implicated in the etiology of ovarian cancer [2]. In addition, it has been reported that endocrine disrupting chemicals (EDCs) may increase the risk of cancer incidence [3,4]. However, the data associated with the effect of EDCs on ovarian cancer cells are scarce.Since EDCs are known as environmental chemicals that interfere with the hormonal balance of vertebrates and invertebrates, they are considered to be important in physiology and the endocrine system [5,6]. EDCs are released from industrial products such as plastics, pesticides, detergents and other synthetic products. It has been proposed that EDCs may increase human health risks and have potentials to affect the immune system and development of vital organs [7][8][9].Bisphenol-A (BPA), alkylphenols, dichloro-diphenyl-trichloroethane (DDT), polychlorinated biphenyls (PCBs) and phthalates are mainly highlighted among EDCs. BPA, a compound used in polycarbonate and epoxy resins, has been implicated as a potent risk factor for women's health [10]. BPA has been widely use...

Bisphenol A Downregulates Akt Signaling and Inhibits Adiponectin Production and Secretion in 3T3-L1 Adipocytes

“…BPA, although less potent than -estradiol (E2), increases heat shock protein (hsp90 ) in the uteri of mice, and ICI 182,780 attenuates BPAand E2-induced increases in uterine hps90 levels 37) . Similar to E2, BPA promotes the growth of several types of cancer cells, and ICI 182,780 effectively abolishes the promoting effect 38,39) . As shown in Fig.…”

Cell growth of BG-1 ovarian cancer cells is promoted by di-n-butyl phthalate and hexabromocyclododecane via upregulation of the cyclin D and cyclin-dependent kinase-4 genes

“…On the other hand, it induces polyovular follicles via ERβ (26). In the present study, we selected BG-1, a human ovarian cancer cell line, to detect the estrogenicity of EDCs as it is a highly estrogen-responsive cell line due to its strong expression of both ERα and ERβ (2,18). We also confirmed its estrogen dependence in the cell proliferation assay, in which the growth of BG-1 cells were increased more than two-fold by a low-dose treatment of E2 (1x10 -9 M).…”

“…Thus, in the present study, we investigated the estrogenic effect of DBP and HBCD in BG-1 ovarian cancer cells which have a high level of ERs to better understand the cellular mechanisms underlying their endocrine-disrupting effect as reported in previous studies. BG-1 is known to be a highly E2-responsive cancer cell line and is considered to be the most suitable in vitro model to detect the estrogenicity of EDCs (2,18). Consequently, we examined the cancer cell proliferation of BG-1 cells via MTT assay and altered expression of genes related to the cell cycle via semi-quantitative reversetranscription PCR following treatment with DBP or HBCD in comparison with E2 in these cells.…”

Adverse Effects on Female Human Reproductive Health from Exposure to Endocrine Disruptors: Focus on Endometrial Lesions

“…The increase of cell proliferation and activation of ERE were reversed in the presence of an estrogen receptor antagonist, ICI 182780 [109]. But how they act?…”