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

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 leptin-induced 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, leptin-induced 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 ERα. 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.

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