Abstract 4562: Inhibition of STAT3 signaling in human liver cancer cells using Evista

Abstract

Abstract Liver cancer is one of the major causes of morbidity and mortality in China and also around the World. Constitutive activation of Signal Transducers and Activators of Transcription 3 (STAT3) signaling is frequently detected in human cancer including liver cancer and has emerged as a viable molecular target for liver cancer treatment. Novel therapeutic approaches of more effective treatments are much needed. To date, few STAT3 inhibitors are available for the therapy of liver cancer yet. Evista (Raloxifene HCI) is used for the prevention and treatment of osteoporosis and was approved for reducing the risk of invasive breast cancer in postmenopausal women with osteoporosis and in postmenopausal women at high risk for invasive breast cancer. We reported the discovery of Raloxifene as novel inhibitors of IL-6/GP130 protein­protein interactions (PPIs) using multiple ligand simultaneous docking (MLSD) and drug repositioning. The possible effect of Evista in STAT3 signaling or liver cancer cells is still unclear. The ability of Evista to inhibit STAT3 was tested. Evista inhibited the P-STAT3 stimulated by IL-6 but not the induction of STAT1, STAT2, and STAT4 phosphorylation by IFN-α and IL-4. Evista inhibited STAT3 phosphorylation and resulted in the induction apoptosis on human liver cancer cell lines HEPG2, 7721, and HUH-7 as evidenced by caspase-3 cleavage. Evista also inhibited the cell viability, cell migration and colony formation in liver cancer cells. Furthermore, administration daily of Evista suppressed the HEPG2 tumor growth in mice in vivo. In summary, our study is the first report indicating that Evista also exhibits biology activity against persistent STAT3 signaling in human liver cancer cells. These results suggest that Evista may also be a chemoprevention agent for liver cancer by targeting persistent STAT3 signaling. Citation Format: Yina Wang, Chongqiang Zhao, Haiyan Ma, Huameng Li, Jiagao Lu, Chenglong Li, Jiayuh Lin, Li Lin. Inhibition of STAT3 signaling in human liver cancer cells using Evista. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4562.