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 |
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Authors: | Eun Hee Han Hyung Gyun Kim Yong Pil Hwang Jae Ho Choi Ji Hye Im Bonghwan Park Ji Hye Yang Tae Cheon Jeong Hye Gwang Jeong |
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Institution: | 1. Department of Toxicology, College of Pharmacy, Chungnam National University, 220 Gung-dong, Daejeon 305-764, Yuseong-Gu, South Korea;2. College of Pharmacy, Chosun University, Gwangju, South Korea;3. College of Pharmacy, Yeungnam University, Kyungsan, South Korea |
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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 E2 (PGE2), 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. |
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Keywords: | CRE cyclic AMP response element COX-2 cyclooxygenase-2 ER estrogen receptor o p&prime -DDT o p&prime -dichlorodiphenyltrichloroethane PGE2 prostaglandin E2 |
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