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

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

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)115620-115631
Number of pages12
JournalOncotarget
Volume8
Issue number70
DOIs
Publication statusPublished - Jan 1 2017

Keywords

  • AR
  • BPA
  • Cell cycle
  • Erk
  • Prostate cancer

ASJC Scopus subject areas

  • Oncology

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  • Cite this

    Bilancio, A., Bontempo, P., Di Donato, M., Conte, M., Giovannelli, P., Altucci, L., Migliaccio, A., & Castoria, G. (2017). Bisphenol a induces cell cycle arrest in primary and prostate cancer cells through EGFR/ERK/p53 signaling pathway activation. Oncotarget, 8(70), 115620-115631. https://doi.org/10.18632/oncotarget.23360