Leptin induces CYP1B1. expression in MCF-7 cells through ligand-independent activation of the ER alpha pathway

Title
Leptin induces CYP1B1. expression in MCF-7 cells through ligand-independent activation of the ER alpha pathway
Author(s)
정태천Khanal T[Khanal T]김형균[김형균]Do MT[Do MT]최재호[최재호]원성수[원성수]강원구정영철[정영철]정혜광[정혜광]
Keywords
ESTROGEN-RECEPTOR-ALPHA; BREAST-CANCER CELLS; ARYL-HYDROCARBON RECEPTOR; DIFFERENTIAL EXPRESSION; EPITHELIAL-CELLS; PROTEIN-KINASE; OBESITY; PHOSPHORYLATION; BETA; STIMULATION
Issue Date
201405
Publisher
ACADEMIC PRESS INC ELSEVIER SCIENCE
Citation
TOXICOLOGY AND APPLIED PHARMACOLOGY, v.277, no.1, pp.39 - 48
Abstract
Leptin, a hormone with multiple biological actions, is produced predominantly by adipose tissue. Among its functions, leptin can stimulate tumour cell growth. Oestrogen receptor alpha (ER alpha), which plays an essential role in breast cancer development, can be transcriptionally activated in a ligand-independent manner. In this study, we investigated the effect of leptin on CYP1B1 expression and its mechanism in breast cancer cells. Leptin induced CYP1B1 protein, messenger RNA expression and promoter activity in ER alpha-positive MCF-7 cells but not in ER alpha-negative MDA-MB-231 cells. Additionally, leptin increased 4-hydroxyoestradiol in MCF-7 cells. Also, ERa knockdown by siRNA significantly blocked the induction of CYP1B1 expression by leptin, indicating that leptin induced CYP1B1 expression via an ER alpha-dependent mechanism. Transient transfection with CYP1B1 deletion promoter constructs revealed that the oestrogen response element (ERE) plays important role in the up-regulation of CYP1B1 by leptin. Furthermore, leptin stimulated phosphorylation of ER alpha at serine residues 118 and 167 and increased ERE-luciferase activity, indicating that leptin induced CYP1B1 expression by ER alpha activation. Finally, we found that leptin activated ERK and Akt signalling pathways, which are upstream kinases related to ER alpha phosphorylation induced by leptin. Taken together, our results indicate that leptin-induced CYP1B1 expression is mediated by ligand-independent activation of the ER alpha pathway as a result of the activation of ERK and Akt in MCF-7 cells. (C) 2014 Elsevier Inc All rights reserved.
URI
http://hdl.handle.net/YU.REPOSITORY/32322http://dx.doi.org/10.1016/j.taap.2014.03.003
ISSN
0041-008X
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약학대학 > 약학부 > Articles
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