193 BISPHENOL A AND PHTHALATE ENHANCED THE GROWTH OF PROSTATE CANCER CELLS AND ALTERED TGF-β SIGNALING MOLECULES VIA AN ESTROGEN RECEPTOR OR ANDROGEN RECEPTOR-DEPENDENT PATHWAY IN IN VITRO AND IN VIVO MODELS

Abstract

Endocrine-disrupting chemicals (EDC) can bind to the hormone receptor and induce an unexpected hormone response to activate oestrogen receptor (ER)- and androgen receptor (AR)-mediated signalling pathways. Among EDC, bisphenol A (BPA) has a detrimental effect on the endocrine system and is suspected to promote human breast and ovarian cancers. Recent studies have reported that phthalate can disrupt the endocrine system and has a weak estrogenic activity with binding to ER. In this study, we demonstrated whether BPA and dibutyl phthalate (DBP) stimulate the proliferation of prostate cancer cells, LNCaP cells, which have both ER and AR. We evaluated the proliferative rate of LNCaP cells following BPA and DBP treatment using a cell viability assay compared with EtOH treatment as a negative control. Further, we examined the alteration of cell cycle-related gene expressions and TGF-β signalling molecules by semiquantitative RT-PCR. Both BPA and DBP increased LNCaP cell growth more than 2-fold. Moreover, these EDC altered transcriptional expressions of cell cycle-related genes, cyclin D1 and p21, at 6 h in LNCaP cells after exposure of BPA and DBP. Like 17β-oestradiol (E2) and dihydrotestosterone (DHP), treatments of BPA and DBP lead to an increase of the transcriptional levels of c-myc and c-fos in LNCaP cells from 30 min to 6 h. In addition, BPA and DBP decreased the protein level of not only p-smad but also total smad, suggesting that these EDC can affect the molecules of the TGF-β signalling pathway. It was of interest that these effects of EDC were reversed by an antagonist of ER or AR signalling pathways in these prostate cancer cells. These results suggest that BPA and phthalate can alter various gene expressions in TGF-β signalling molecules and stimulate cell growth in prostate cancer cells in vitro. In addition, the growth of prostate cancer cells was stimulated following the exposure of E2, DHT, and DBP in vivo. Taken together, these results indicate the potential of BPA and phthalate in the carcinogenesis of prostate cancer by the oestrogen or androgen-dependent signalling pathway.

This work was supported by a National Research Foundation of Korea (NRF) grant funded by the Ministry of Education, Science and Technology (MEST) of Korea government (no. 2011-0015385).