Taking all the data together we propose
Taking all the data together, we propose the possible mechanism of glyphosate-induce cell proliferation via estrogen receptor signaling (Fig. 10). Glyphosate may bind to ERα followed by an activation step that starts with the phosphorylation of ERα and activation of other signaling proteins by phosphorylation or some other mechanisms. The signaling proteins involved in this mechanism include ERK, PI3K(p85), 2881 D1 and cyclin A. The results of estrogen signaling activation may induce gene and protein expression of other proteins, include ERα, VEGFR2, and PCNA.
Estrogen receptors have been shown to mediate the growth and aggressiveness of several cancers, not only in breast cancer but also other cell types, such as cholangiocarcinoma. Thus, any chemical that can modulate estrogen receptor activities could contribute as a risk factor of etiology and progression of the cancers. Several studies have suggested that the environmental chemicals may be one of the factors that can cause CCA (Patel, 2011). Glyphosate is one of common herbicides and also the number one imported chemical into Thailand (Apiwat et al., 2014). There are high risks of glyphosate contamination in the environment and increased risk of exposure to this chemical as reported by Kongtip et al. (2017). The results obtained from the present study explain, at least in part, how glyphosate act on the estrogen signaling pathway in inducing proliferation of cholangiocarcinoma cells.
Conflicts of interest
Acknowledgements The authors would like to thank Dr.Daam Settachan for English editing of the manuscript. We would like to thank Ms.Kanjana Chaiyot for the technical assistance on cell culture; Mrs. Daranee Visitnonthachai for the technical assistance on flow cytometry. This work was funded by The Chulabhorn Research Institute [CRI-PH2015-01/03] and in part by the grant from Center of Excellence on Environmental Health and Toxicology, Science & Technology Postgraduate Education and Research Development Office (PERDO), Ministry of Education [EHT-Prog.5-60].
Introduction 1,25(OH)2-vitamin D3 has been vastly assessed for its suppressive effects on breast cancer cell proliferation via binding with the vitamin D receptor (VDR). VDR itself is the subject of regulation by numerous including the its functional ligand as well as various steroid hormones (Davoodi et al., 1995). The interaction between 1,25(OH)2-vitamin D3, vitamin D receptor (VDR) and receptors for other steroid hormones such as estrogen receptor (ER) has been studied for a long time. The effects of 1,25(OH)2-vitamin D3 on VDR can be exerted through both increasing its mRNA (Strom et al., 1989) and stabilizing its structure (Wiese et al., 1992). On the other hand, 1,25(OH)2-vitamin D3 has a cell line specific effect on expression of ER. While in T-47D cells it does not regulate ER expression either at transcriptional or at post-transcriptional levels (Davoodi et al., 1995), in MCF-7 human breast cancer cells, 1,25(OH)2-vitamin D3 decreases both mRNA level and function of ER (Stoica et al., 1999) through inhibition of ER binding to estrogen response elements (Demirpence et al., 1994). In MDA-MB-231 cells, treatment with 1,25(OH)2- vitamin D3 possibly enhances expression of other estrogen binding proteins rather than ER (Davoodi et al., 1995). On the other hand, 17 beta-estradiol (E2) up-regulates expression of VDR through binding with its receptors localized in membranal caveolar domains in HT29 and MCF-7 cells and subsequent stimulation of ERK 1/2 (Gilad et al., 2005). Further supports for interaction between VDR and ER signaling have emerged from clinical studies. Yao et al. have demonstrated a significant association between serum levels of 25- hydroxy vitamin D (25OHD) and decreased risk of ER negative and triple-negative breast cancer subtypes (Yao et al., 2011). Al-Azhri et al. have shown lower VDR expression in ER negative breast tumor samples compared with ER positive samples (Al-Azhri et al., 2017).