Estrogen receptor alpha pathway is involved in leptin-induced ovarian cancer cell growth

Abstract

Previously, we demonstrated that leptin, a pleiotropic hormone produced by adipocytes, stimulates the growth of BG-1 ovarian cancer cells via the extracellular signal-regulated kinase signaling pathway. In this study, we further investigated the involvement of estrogen receptor (ER) pathway in the mechanism of leptininduced ovarian cancer cell growth. Treatment with leptin (100 ng/ml) resulted in a significant increase in the cell growth of ERα-transfected OVCAR-3 and A2780 cells, whereas no significant difference was observed in ERβ-transfected cells. Downregulation of ERα using small interfering RNA completely reversed leptin-induced growth of BG-1 cells. Treatment with leptin resulted in ER transcriptional activation, i.e. nuclear localization of ER and increased expression of pS2, an estrogen-dependent gene. Luciferase reporter assay revealed that treatment of BG-1 cells with leptin (100 ng/ml) stimulated the expression of the reporter gene in the absence of estradiol (E2). To examine an involvement of Janus kinase 2/signal transducers and activators of transcription 3 (STAT-3) and phosphatidyl-inositol 3-kinase (PI3K)/Akt in leptin-induced pathway, we demonstrated that leptin increased phosphorylation of STAT-3 and Akt in BG-1 cells in a time- and dose-dependent manner. On the other hand, leptininduced cell growth and ER transactivation were effectively blocked by specific STAT-3 inhibitor AG490 and, to a lesser extent, by PI3K inhibition. Further study with coimmunoprecipitation assay revealed that stimulation with leptin induced STAT-3 binding to ERa. Taken together, these results indicate that the stimulation of ovarian cancer cell growth by leptin involves, at least in part, ER transcriptional activation via the STAT-3 signaling pathways. © The Author 2010. Published by Oxford University Press. All rights reserved.