Bisphenol A stimulates human lung cancer cell migration via upregulation of matrix metalloproteinases by GPER/EGFR/ERK1/2 signal pathway

Biomed Pharmacother. 2014 Oct;68(8):1037-43. doi: 10.1016/j.biopha.2014.09.003. Epub 2014 Sep 18.


Lung cancer is one of the leading causes of cancer deaths worldwide. Recent evidences indicated that bisphenol A (BPA), a wide contaminant with endocrine disrupting activity, could enhance the susceptibility of carcinogenesis. Although there are increasing opportunities for lung cells exposure to BPA via inhalation, there is no study concerning the effects of BPA on the development of lung cancer. The present study revealed that BPA less than 10(-4)M had limited effects on the proliferation of lung cancer A549 cells, however, BPA treatment significantly stimulated the in vitro migration and invasion of cells combing with the morphological changes and up regulation of matrix metalloproteinase-2 (MMP-2) and MMP-9. G-protein-coupled estrogen receptor (GPER), while not estrogen receptor α/β (ERα/β), mediated the BPA induced up regulation of MMPs. Further, BPA treatment induced rapid activation of ERK1/2 via GPER/EGFR. GPER/ERFR/ERK1/2 mediated the BPA induced upregulation of MMPs and in vitro migration of lung cancer A549 cells. In summary, our data presented here revealed for the first time that BPA can promote the in vitro migration and invasion of lung cancer cells via upregulation of MMPs and GPER/EGFR/ERK1/2 signals, which mediated these effects. This study suggested that more attention should be paid on the BPA and other possible environmental estrogens induced development of lung cancer.

Keywords: BPA; Lung cancer; MMP; Migration.

MeSH terms

  • Benzhydryl Compounds / toxicity*
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Movement / physiology*
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Dose-Response Relationship, Drug
  • ErbB Receptors / biosynthesis*
  • Estrogens, Non-Steroidal / toxicity
  • Humans
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • MAP Kinase Signaling System / drug effects
  • MAP Kinase Signaling System / physiology*
  • Matrix Metalloproteinases / biosynthesis*
  • Phenols / toxicity*
  • Receptors, Estrogen / biosynthesis*
  • Receptors, G-Protein-Coupled / biosynthesis*
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Up-Regulation / drug effects
  • Up-Regulation / physiology


  • Benzhydryl Compounds
  • Estrogens, Non-Steroidal
  • GPER1 protein, human
  • Phenols
  • Receptors, Estrogen
  • Receptors, G-Protein-Coupled
  • EGFR protein, human
  • ErbB Receptors
  • Matrix Metalloproteinases
  • bisphenol A