G-protein-coupled receptor 30 and estrogen receptor-alpha are involved in the proliferative effects induced by atrazine in ovarian cancer cells.
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 17beta-estradiol and environmental estrogens.


OBJECTIVE
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.


RESULTS
Atrazine did not transactivate the endogenous ERalpha in different cancer cell contexts or chimeric proteins encoding the ERalpha and ERbeta hormone-binding domain in gene reporter assays. Moreover, atrazine neither regulated the expression of ERalpha 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 ERalpha.


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.
Albanito
Lidia
L
Department of Pharmaco-Biology, University of Calabria, Rende, Italy.
Lappano
Rosamaria
R
Madeo
Antonio
A
Chimento
Adele
A
Prossnitz
Eric R
ER
Cappello
Anna Rita
AR
Dolce
Vincenza
V
Abonante
Sergio
S
Pezzi
Vincenzo
V
Maggiolini
Marcello
M
D001141:Aromatase / Q000378:metabolism; D001280:Atrazine / Q000633:toxicity*; D001483:Base Sequence; D049109:Cell Proliferation / Q000187:drug effects; D017931:DNA Primers; D004789:Enzyme Activation; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005260:Female; D006540:Herbicides / Q000633:toxicity*; D006801:Humans; D010051:Ovarian Neoplasms / Q000473:pathology* / Q000503:physiopathology; D010766:Phosphorylation; D011960:Receptors, Estrogen / Q000502:physiology*; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D014407:Tumor Cells, Cultured
D017931:DNA Primers; D006540:Herbicides; D011960:Receptors, Estrogen; D043562:Receptors, G-Protein-Coupled; D001141:Aromatase; D048049:Extracellular Signal-Regulated MAP Kinases; D001280:Atrazine