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Lidia Albanito,^1,* Rosamaria Lappano,^1,* Antonio Madeo,¹ Adele Chimento,¹ Eric R. Prossnitz,² Anna Rita Cappello,¹ Vincenza Dolce,¹ Sergio Abonante,¹ Vincenzo Pezzi,¹ and Marcello Maggiolini¹

¹Department of Pharmaco-Biology, University of Calabria, Rende, Italy; ²Department of Cell Biology and Physiology and Cancer Research and Treatment Center, University of New Mexico, Albuquerque, New Mexico, USA

Abstract
Background: Atrazine, one of the most common pesticide contaminants, has been shown to up-regulate aromatase activity in certain estrogen-sensitive tumors without binding or activating the estrogen receptor (ER) . Recent investigations have demonstrated that the orphan G-protein–coupled receptor 30 (GPR30) , which is structurally unrelated to the ER, mediates rapid actions of 17β-estradiol and environmental estrogens.

Objectives: Given the ability of atrazine to exert estrogen-like activity in cancer cells, we evaluated the potential of atrazine to signal through GPR30 in stimulating biological responses in cancer cells.

Methods and results: Atrazine did not transactivate the endogenous ERα in different cancer cell contexts or chimeric proteins encoding the ERα and ERβ hormone-binding domain in gene reporter assays. Moreover, atrazine neither regulated the expression of ERα nor stimulated aromatase activity. Interestingly, atrazine induced extracellular signal-regulated kinase (ERK) phosphorylation and the expression of estrogen target genes. Using specific signaling inhibitors and gene silencing, we demonstrated that atrazine stimulated the proliferation of ovarian cancer cells through the GPR30–epidermal growth factor receptor transduction pathway and the involvement of ERα.

Conclusions: Our results indicate a novel mechanism through which atrazine may exert relevant biological effects in cancer cells. On the basis of the present data, atrazine should be included among the environmental contaminants potentially able to signal via GPR30 in eliciting estrogenic action.

Key words: 17β-estradiol, atrazine, estrogen receptor, GPR30, ovarian cancer cells. Environ Health Perspect 116:1648–1655 (2008) .  doi:10.1289/ehp.11297 available via http://dx.doi.org/ [Online 22 July 2008]

Address correspondence to M. Maggiolini, Department of Pharmaco-Biology, University of Calabria, 87030 Rende (CS) , Italy. Telephone: 390984493076. Fax: 390984493458. E-mail: marcellomaggiolini@yahoo.it

*These authors contributed equally to this work.

This research was supported by grants from the Associazione Italiana per la Ricerca sul Cancro, Ministero dell'Università e Ricerca Scientifica e Tecnologica, and Regione Calabria.

The authors declare they have no competing financial interests.

Received 28 January 2008 ; accepted 18 July 2008.