Activated oestrogen receptor (ER) signaling pathway by 17β-estadiol (E2) appeared to suppress transforming growth factor β (TGF-β) signaling pathway by cross-talk with TGF-β components in ER-positive cancer cells. In this study, we further examined the inhibitory effects of alkylphenols, including 4-nonylphenol (NP), 4-otylphenol (OP), bisphenol A (BPA), and benzophenon-1 (BP-1), in TGF-β signaling pathway. The transcriptional and translational levels of TGF-β-related genes were examined by reverse-transcription PCR (RT-PCR), Western blotting analysis in xenografted mouse models of ovarian cancer BG-1 cells. The NP, OP, and BPA induced the expression of snoN, a TGF-β pathway inhibitor. Treatment with NP, BPA, and BP-1 resulted in decreased phosphorylation of Smad3, a downstream target of TGF-β. With these 2 effects, NP and BPA stimulated the proliferation of BG-1 cells via inhibition of the TGF-β signaling pathway. In a xenograft mouse model, transplanted BG-1 ovarian cancer cells showed significantly decreased phosphorylation of Smad3 and increased expression of snoN in the ovarian tumour masses following treatment with E2, NP, or BPA. In parallel with an in vitro model, the expressions of TGF-β signaling pathway were similarly regulated by NP or BPA in a xenograft mouse model, revealing consistent results. Taken together, these results support that NP and BPA may cause the disruption of the TGF-β signaling pathway and increase the risk of oestrogen-dependent cancers such as ovarian cancer.
This work was supported by a grant from the Next-Generation BioGreen 21 Program (No. PJ009599), Rural Development Administration, Republic of Korea.
Fibroblast-specific perturbation of transforming growth factor β signaling provides insight into potential pathogenic mechanisms of scleroderma-associated lung fibrosis: Exaggerated response to alveolar epithelial injury in a novel mouse model