The role of cyclooxygenase-2-dependent signaling via cyclic AMP response element activation on aromatase up-regulation by o,p'-DDT in human breast cancer cells

Title
The role of cyclooxygenase-2-dependent signaling via cyclic AMP response element activation on aromatase up-regulation by o,p'-DDT in human breast cancer cells
Author(s)
한은희[한은희]김형균[김형균]황용필[황용필]최재호[최재호]임지혜[임지혜]박봉환[박봉환]양지혜[양지혜]정태천정혜광[정혜광]
Keywords
HORMONE-RECEPTOR STATUS; GENE-EXPRESSION; ESTROGEN BIOSYNTHESIS; CYP19 EXPRESSION; PROMOTER II; P450 GENE; COX-2; INDUCTION; TISSUE; TRANSCRIPTION
Issue Date
201010
Publisher
ELSEVIER IRELAND LTD
Citation
TOXICOLOGY LETTERS, v.198, no.3, pp.331 - 341
Abstract
o,p'-Dichlorodiphenyltrichloroethane (o,p'-DDT) is a DDT isomer and xenoestrogen that can induce inflammation and cancer. However, the effect of o,p'-DDT on aromatase is unclear. Thus, we investigated the effects of o,p'-DDT on aromatase expression in human breast cancer cells. We also examined whether cyclooxygenase-2 (COX-2) is involved in o,p'-DDT-mediated aromatase expression. Treatment with o,p'-DDT-induced aromatase protein expression in MCF-7 and MDA-MB-231 human breast cancer cells; enhancing aromatase gene expression, and enzyme and promoter activity. Treatment with ICI 182.780, a estrogen receptor antagonist, did not affect the inductive effects of o,p'-DDT on aromatase expression. In addition, o,p'-DDT increased COX-2 protein levels markedly, increased COX-2 mRNA expression and promoter activity, enhanced the production of prostaglandin E-2 (PGE(2)), induced cyclic AMP response element (CRE) activation, and cAMP levels and binding of CREB. o,p'-DDT also increased the phosphorylation of PKA, Akt, ERK, and JNK in their signaling pathways in MCF-7 and MDA-MB-231 cells. Finally, o,p'-DDT induction of aromatase was inhibited by various inhibitors [COX-2 (by NS-398), PKA (H-89), PI3-K/Akt (LY 294002), EP2 (AH6809), and EP4 receptor (AH23848)]. Together, these results suggest that o,p'-DDT increases aromatase, and that o,p'-DDT-induced aromatase is correlated with COX-2 up-regulation, mediated via the CRE activation and PKA and PI3-kinase/Akt signaling pathways in breast cancer cells. 2010 Elsevier Ireland Ltd. All rights reserved.
URI
http://hdl.handle.net/YU.REPOSITORY/23486http://dx.doi.org/10.1016/j.toxlet.2010.07.015
ISSN
0378-4274
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약학대학 > 약학부 > Articles
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