The activation of leptin-mediated survivin is limited by the inducible suppressor SOCS-3 in MCF-7 cells

Abstract

Although leptin has been found to be implicated in obesity-related breast carcinogenesis in postmenopausal women, the molecular mechanisms involved are yet to be defined. Recently, the antiapoptotic gene survivin has been recognized as a target gene for leptin in breast cancer. The aim of this study was to investigate the effect of leptin on the expression of survivin and on the transcriptional activity of its promoter in MCF-7 breast cancer cells. We also studied the potential involvement of SOCS-3 (a negative regulator of leptin's main signaling pathway JAK2/STAT3) in the expression of leptin-mediated survivin. Our results showed a significant increase in the mRNA (dose-dependent increase of 40-70%) and protein expression levels of survivin 24 h post-leptin treatment, which was followed by a significant decrease at 48 and 72 h (of 60-70%). In accordance, a chromatin immunoprecipitation assay revealed an initial strong binding of STAT3 to the survivin promoter, which was no longer detected after 24 h. Myc/mad/max network proteins and histone H3 acetylation status were not found to contribute to the expression of leptin-mediated survivin. Furthermore, a protein immunoprecipitation assay detected an enhanced SOCS-3 binding to the long isoform of leptin's receptor (Ob-Rb) 48 and 72 h after leptin administration, thus conferring inhibition to leptin signaling. In conclusion, our findings suggest, for the first time to our knowledge, that the effect of leptin on the antiapoptotic gene survivin is limited by the inhibitory role of SOCS-3 in the leptin-activated JAK2/STAT3 signaling pathway in MCF-7 breast cancer cells.