Two isoforms of intracellular ER
Two isoforms of intracellular ER, ERα, and ERβ, after binding to estrogens and translocate to the nucleus, activate some transcription factors and signaling pathways. The deregulation of estrogenic pathways can elevate transcriptional activity contributed to the development of cancer. Expression of ER is associated with a degree of differentiation and cell proliferation speed of tumor (Guo and Sonenshein, 2004; Oh et al., 2001).
Several investigations indicated that Cd as a metaloesterogen can bind and activate ER and induce not only expression of specific ER target genes but also other estrogen-like effects such as increasing the growth of breast cancer pitavastatin (Brama et al., 2007), ovarian cancer cells (Nampoothiri and Gupta, 2006) and increased cell proliferation in rat uterine cells (Aquino et al., 2012). Some reports show that Cd stimulates transcription of several estrogen-inducible genes like progesterone receptor, some proto-oncogenes and transcription factors such as c-fos, c-jun, and FOXO3a. Moreover, Cd up-regulates some signaling pathway kinases and increases phosphorylation of extracellular signal-regulated kinases involved in regulation of cell growth/proliferation, metastasis, and apoptosis (Brama et al., 2007). The deregulation of ERK/MAPK pathway plays a critical role in carcinogenesis and provides estrogen-dependent signaling in tumor growth (Filardo et al., 2002). Recent studies have shown that ERK cascade activity increases almost in one-third of all human cancers. Moreover, the inhibition of components of this cascade can be consider as an important anti-tumor strategy (Roskoski, 2012). Although some studies have demonstrated that Cd accumulates and concentrates in ovarian tissue, there are still no studies on the association between Cd exposure and the etiology of ovarian cancer. Furthermore, the mechanism whereby Cd causes the cell proliferation remains poorly understood and no uniform outcome has been pulled out with respect to the cellular signaling pathways suggested in proliferation induced by Cd. So this study aims to evaluate the estrogenic effect of Cd on the cell proliferation of ovarian cancer and determine the underlying mechanism.
Material and methods
Discussion Cd was introduced as a xenoestrogen which mimics estrogen effects, disrupts the endocrine system (Joseph, 2009), activates the ER, alters the expression of various estrogen target genes (Johnson et al., 2003; Siewit et al., 2010) and also associates with the occurrence and development of typical estrogen-related cancers such as breast, endometrial and ovarian cancers (Adams et al., 2014; Hartwig, 2013). Cd is known as a reproductive toxicant which accumulates in ovary and uterus and causes some toxicity effects (Nampoothiri and Gupta, 2006). The function of estrogens in the etiology of ovarian cancer and estrogen-mimicking properties of Cd suggest a role of this metal in ovarian malignancy (Spillman et al., 2010; Syed et al., 2001). In the present study, we investigated the effect of various concentrations of Cd on the proliferation of ovarian cancer cell lines. Our results show that Cd significantly increased cell proliferation at nM concentration but markedly inhibited cell growth at μM concentration in a biphasic dose-response manner. Previous studies have shown a biphasic effect of Cd on cell proliferation in human embryo lung fibroblast cells and human embryonic kidney cells (Jiang et al., 2008, Jiang et al., 2009). The results of Hao et al. demonstrated that Cd and Hg stimulated cell proliferation at 0.05 and 0.5 μM but inhibited it at 50 and 500 μM in breast cancer cell lines (Hao et al., 2009). Gao et al. explored that CdCl2 stimulated the proliferation of uterine cancer cell line at lower concentrations (0.1 μM and 10 μM) and it inhibited proliferation at concentrations ≥50 μM (Gao et al., 2015). Khojastehfar et al. concluded that nM concentration of Cd enhanced MCF7 cell proliferation but μM concentration of this heavy metal-induced cell apoptosis by elevation of ROS level in a dose-dependent manner (Khojastehfar et al., 2015). More recent studies in breast, prostate, mesangial and lung epithelial cell lines indicated that low concentrations of Cd promoted cell growth (Bakshi et al., 2008; Kundu et al., 2009; Wei et al., 2015). The results of Huff et al. showed that both CdCl2 and NaAsO2 at nM concentrations, environmentally relevant concentrations, have proliferative effect in some types of lung cancer cell lines (Huff et al., 2016).