Rapid activation of ERK1/2 and AKT in human breast cancer cells by cadmium.

Abstract

Cadmium (Cd), an endocrine disruptor, can induce a variety of signaling events including the activation of ERK1/2 and AKT. In this study, the involvement of estrogen receptors (ER) in these events was evaluated in three human breast cancer cell lines, MCF-7, MDA-MB-231, and SK-BR-3. The Cd-induced signal activation patterns in the three cell lines mimicked those exhibited in response to 17 beta-estradiol. Specifically, treatment of MCF-7 cells, that express ER alpha, ER beta and GPR30, to 0.5-10 microM Cd for only 2.5 min resulted in transient phosphorylation of ERK1/2. Cd also triggered a gradual increase and sustained activation of AKT during the 60 min treatment period. In SK-BR-3 cells, that express only GPR30, Cd also caused a transient activation of ERK1/2, but not of AKT. In contrast, in MDA-MB-231 cells, that express only ER beta, Cd was unable to cause rapid activation of either ERK1/2 or AKT. A transient phosphorylation of ER alpha was also observed within 2.5 min of Cd exposure in the MCF-7 cells. While the estrogen receptor antagonist, ICI 182,780, did not prevent the effect of Cd on these signals, specific siRNA against hER alpha significantly reduced Cd-induced activation of ERK1/2 and completely blocked the activation of AKT. It is concluded that Cd, like estradiol, can cause rapid activation of ERK1/2 and AKT and that these signaling events are mediated by possible interaction with membrane ER alpha and GPR30, but not ER beta.

• Authors: Zhiwei Liu, Xinyuan Yu, Zahir A Shaikh
• Journal: Toxicology and applied pharmacology (Toxicol Appl Pharmacol) Vol. 228 Issue 3 Pg. 286-94 (May 01 2008) ISSN: 0041-008X [Print] United States
• PMID: 18275979 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Endocrine Disruptors
• Estrogen Antagonists
• Estrogen Receptor alpha
• RNA, Small Interfering
• Cadmium
• Proto-Oncogene Proteins c-akt
• Mitogen-Activated Protein Kinase 1
• Mitogen-Activated Protein Kinase 3

Topics

• Breast Neoplasms (metabolism, pathology)
• Cadmium (toxicity)
• Cell Line, Tumor
• Endocrine Disruptors (toxicity)
• Enzyme Activation (drug effects)
• Estrogen Antagonists (pharmacology)
• Estrogen Receptor alpha (metabolism)
• Female
• Humans
• Mitogen-Activated Protein Kinase 1 (metabolism)
• Mitogen-Activated Protein Kinase 3 (metabolism)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA, Small Interfering (pharmacology)