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.
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.
Han
Eun Hee
EH
Department of Toxicology, College of Pharmacy, Chungnam National University, 220 Gung-dong, Daejeon 305-764, Yuseong-Gu, South Korea.
Kim
Hyung Gyun
HG
Hwang
Yong Pil
YP
Choi
Jae Ho
JH
Im
Ji Hye
JH
Park
Bonghwan
B
Yang
Ji Hye
JH
Jeong
Tae Cheon
TC
Jeong
Hye Gwang
HG
D001141:Aromatase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000201:enzymology / Q000378:metabolism*; D050882:CREB-Binding Protein / Q000378:metabolism*; D045744:Cell Line, Tumor; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D003634:DDT / Q000494:pharmacology*; D015232:Dinoprostone / Q000378:metabolism; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D012313:RNA / Q000737:chemistry / Q000235:genetics; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D018078:Receptors, Prostaglandin E / Q000235:genetics / Q000378:metabolism; D058309:Receptors, Prostaglandin E, EP4 Subtype; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
D004791:Enzyme Inhibitors; C545650:PTGER4 protein, human; D011960:Receptors, Estrogen; D018078:Receptors, Prostaglandin E; D058309:Receptors, Prostaglandin E, EP4 Subtype; D012313:RNA; D003634:DDT; C016340:o,p'-DDT; D001141:Aromatase; D051546:Cyclooxygenase 2; D050882:CREB-Binding Protein; C494363:CREBBP protein, human; D015232:Dinoprostone