Bisphenol A induces cell cycle arrest in primary and prostate cancer cells through EGFR/ERK/p53 signaling pathway activation.

Antonio Bilancio,Lucia Altucci,Paola Bontempo,Antimo Migliaccio,Mariarosaria Conte,Pia Giovannelli,Marzia Di Donato,Gabriella Castoria

doi:10.18632/oncotarget.23360

Abstract

Bisphenol A (BPA) belongs to the class of chemicals known as endocrine disruptors and has been also involved in the pathogenesis and progression of endocrine related cancer such as breast and prostate cancers. Here, we have investigated the effect of BPA in human prostate cancer LNCaP cells and in human non-transformed epithelial prostate EPN cells. Our data showed that BPA induces the down regulation of cyclin D1 expression and the upregulation of the cell cycle inhibitors p21 and p27, leading to cell cycle arrest. Interestingly, we found that the BPA anti-proliferative response depends on a strong and rapid activation of epidermal growth factor receptor (EGFR), which stimulates ERK-dependent pathway. This, in turn, induces expression of p53 and its phosphorylation on residue Ser15, which is responsible for cell cycle arrest. EGFR activation occurs upon a cross talk with androgen (AR) and estradiol receptor-β (ERβ) which are known to bind BPA.Altogether, these findings show a novel signaling pathway in which EGFR activation plays a key role on BPA-induced cell cycle inhibition through a pathway involving AR and ERβ/EGFR complexes, ERK and p53. Our results provide new insights for understanding the molecular mechanisms in human prostate cancer. On the other, they could allow the development of new compounds that may be used to overcome human prostate cancer resistance to endocrine therapy in promising target therapeutic approaches.

Highlights

Bisphenol A (BPA; 4, 40-dihydroxy-2, 2 diphenylpropane; CAS 80-05-7) is an organic compound well known by chemists and biologists since the end of 19th century
Based on this observation that BPA can have different effects depending on the cells used, we evaluated the effects of BPA in LNCaP, a cancer cell line derived from human epithelial prostate cancer
Treatment with 10, 50 and 100 μM BPA altered LNCaP cells morphology from cobblestone-like to a rounded shaped in a dose-dependent manner compared with control experiments where we found no differences in cellular size and/or morphology (Figure 1A)

Summary

Introduction

Bisphenol A (BPA; 4, 40-dihydroxy-2, 2 diphenylpropane; CAS 80-05-7) is an organic compound well known by chemists and biologists since the end of 19th century. Only recently BPA has been reported to have hormonal effects in reproductive organs of female rat [1]. BPA has attracted great interest in the chemical industry as it is still currently used as a monomer in the production of plastic polymers, such as polycarbonate, and as a regulator of polyvinyl chloride polymerization. These materials are commonly used for the production of a huge amount of consumer products including, first of all, plastic bottles, feeding bottles, some medical devices, and many others. In recent years increasing attention has been given to BPA since a very relevant amounts of BPA (even higher than 1mg/kg) have been detected in some foods, like vegetables, probably as consequence of leak from plastic irrigation devices [1,2,3,4,5,6]

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