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

Albanito L, Lappano R, Madeo A, Chimento A, Prossnitz ER, Cappello AR, Dolce V, Abonante S, Pezzi V, Maggiolini M - Environ. Health Perspect. (2008)

Bottom Line: Moreover, atrazine neither regulated the expression of ERalpha nor stimulated aromatase activity.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaco-Biology, University of Calabria, Rende, Italy.

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 17beta-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 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.

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Related in: MedlinePlus

Immunoblots of c-fos from BG-1 (A,B) and 2008 (C,D) cells treated for 2 hr with vehicle (−), 100 nmol/L E2, or 1 μmol/L atrazine (Atr) in combination with 10 μmol/L ICI, AG, PD, GFX, H89, or WM, inhibitors of ER, EGFR, MEK, PKC, PKA, and PI3K, respectively. β-Actin served as a loading control.
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f8-ehp-116-1648: Immunoblots of c-fos from BG-1 (A,B) and 2008 (C,D) cells treated for 2 hr with vehicle (−), 100 nmol/L E2, or 1 μmol/L atrazine (Atr) in combination with 10 μmol/L ICI, AG, PD, GFX, H89, or WM, inhibitors of ER, EGFR, MEK, PKC, PKA, and PI3K, respectively. β-Actin served as a loading control.

Mentions: Using c-fos expression as a molecular sensor of atrazine action at the genomic level, we sought to determine whether c-fos protein levels are also regulated by atrazine in a rapid manner and the transduction pathways involved in this response (Figure 8). Interestingly, the up-regulation of c-fos observed in BG-1 and 2008 cells after a short treatment (2 hr) was abolished by the ER antagonist ICI, the EGFR inhibitor AG, or the ERK inhibitor PD (Figure 8). On the contrary, GFX, H89, and WM, inhibitors of PKC, PKA, and PI3K, respectively, did not interfere with c-fos stimulation (Figure 8). Thus, in ovarian cancer cells, atrazine involves ERα and the EGFR/MAPK pathway to trigger c-fos protein increase.


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

Albanito L, Lappano R, Madeo A, Chimento A, Prossnitz ER, Cappello AR, Dolce V, Abonante S, Pezzi V, Maggiolini M - Environ. Health Perspect. (2008)

Immunoblots of c-fos from BG-1 (A,B) and 2008 (C,D) cells treated for 2 hr with vehicle (−), 100 nmol/L E2, or 1 μmol/L atrazine (Atr) in combination with 10 μmol/L ICI, AG, PD, GFX, H89, or WM, inhibitors of ER, EGFR, MEK, PKC, PKA, and PI3K, respectively. β-Actin served as a loading control.
© Copyright Policy - public-domain
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2599758&req=5

f8-ehp-116-1648: Immunoblots of c-fos from BG-1 (A,B) and 2008 (C,D) cells treated for 2 hr with vehicle (−), 100 nmol/L E2, or 1 μmol/L atrazine (Atr) in combination with 10 μmol/L ICI, AG, PD, GFX, H89, or WM, inhibitors of ER, EGFR, MEK, PKC, PKA, and PI3K, respectively. β-Actin served as a loading control.
Mentions: Using c-fos expression as a molecular sensor of atrazine action at the genomic level, we sought to determine whether c-fos protein levels are also regulated by atrazine in a rapid manner and the transduction pathways involved in this response (Figure 8). Interestingly, the up-regulation of c-fos observed in BG-1 and 2008 cells after a short treatment (2 hr) was abolished by the ER antagonist ICI, the EGFR inhibitor AG, or the ERK inhibitor PD (Figure 8). On the contrary, GFX, H89, and WM, inhibitors of PKC, PKA, and PI3K, respectively, did not interfere with c-fos stimulation (Figure 8). Thus, in ovarian cancer cells, atrazine involves ERα and the EGFR/MAPK pathway to trigger c-fos protein increase.

Bottom Line: Moreover, atrazine neither regulated the expression of ERalpha nor stimulated aromatase activity.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Pharmaco-Biology, University of Calabria, Rende, Italy.

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 17beta-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 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.

Show MeSH
Related in: MedlinePlus