Abstract 5282: Leptin induces Notch in endothelial cells: Role of VEGFR-2 transactivation

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Notch signaling is essential for breast cancer (BC) angiogenesis and its dysfunction is implicated in many cancers. Leptin (a pro-angiogenic, pro-inflammatory and mitogenic factor) induces the expression of VEGF/VEGFR-2 and Notch in BC cells. Moreover, the binding of leptin to its receptor (OB-Rb) in endothelial cells (EC) was shown to phosphorylate/transactivate VEGFR-2 inducing angiogenic features. We hypothesize that leptin is an inducer of Notch in EC and that this effect could occur upon leptin-mediated transactivation of VEGFR-2, thereby inducing angiogenic changes in EC. To this end, HUVEC cells were challenged with leptin, leptin inhibitor (LPrA2) VEGFR-2 kinase inhibitor (SU5416) and Notch signaling inhibitor (DAPT). Leptin-dose and time-course effects on expression of Notch (receptors: Notch1, Notch2, Notch3 and Notch4; ligands: JAG1, Dll-4 and targets: survivin and Hey2) were determined by WB and real time RT-PCR. The impact of LPrA2, SU5416 and DAPT on leptin-induced VEGFR-2 phosphorylation and Notch expression was also determined. The effects of leptin and inhibitors on EC proliferation, migration and tube formation were investigated. Results from our studies show for the first time that leptin is a potent inducer of Notch signaling in EC. Moreover, leptin-induced VEGFR-2 phosphorylation was closely related to leptin effects on Notch and the angiogenic features of EC. Therefore, leptin secreted either by adipose tissue or BC cells may contribute to tumor angiogenesis by acting directly on cancer cells inducing VEGF secretion or through EC inducing VEGFR-2/Notch crosstalk. Present results underline the notion that combinatory therapies targeting both Notch and leptin signaling could be a new strategy for BC treatment. [This work was supported in part by NIH/NCI1SC1CA138658-02; NIH/ARRA/3SC1CA138658-02S1 and the Georgia Cancer Coalition Distinguished Cancer Scholar Award (to RRGP)]. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5282. doi:1538-7445.AM2012-5282