Abstract 3252: A novel small molecule, LY5, selectively inhibits STAT3 phosphorylation and activities and exhibits potent growth suppressive activity in cancer cells.

Abstract

Abstract In response to cytokines and growth factors, Signal Transducers and Activators of Transcription 3 (STAT3) signaling is activated which plays a critical role in oncogenesis, proliferation, survival, and invasion of various human cancers and cancer cell lines. Numerous evidences have demonstrated that inhibition of STAT3 signaling pathway results in decreased growth and apoptosis in human cancer cells. This makes STAT3 an excellent molecular target for cancer therapy. In this study, we investigated a novel non-peptide, cell-permeable, small molecule, named as LY5, which selectively targets STAT3. LY5 inhibited constitutive STAT3 activation in various human pediatric sarcoma and medulloblastoma cell lines expressing elevated levels of STAT3 phosphorylation. LY5 also blocked STAT3 phosphorylation induced by Interleukin-6, IGF-1, and OSM in SJSA human osteosarcoma cells, but did not inhibit STAT1, STAT2, STAT4, and STAT6 phosphorylation stimulated by interferon (IFN)-γ,IFN-α, and IL-4, respectively. Furthermore, LY5 suppressed the induction of STAT3 nuclear localization by IL-6, which could prevent STAT3 function as a transcription factor, but not STAT1 nuclear localization induced by IFN-γ. In addition, LY5 induced apoptosis in sarcoma and medulloblastoma cells as indicated by the increases of cleaved caspase-3, but LY5 did not induce apoptosis in normal primary human cells. The inhibition of STAT3 signaling by LY5 was further confirmed by down-regulating the expression of the downstream targets of STAT3, including cyclin D1, Bcl-XL, and survivin. Taken together, these findings indicated LY5 selectively inhibited constitutive STAT3 activation and suggested that LY5 is a promising therapeutic candidate for pediatric sarcoma and medulloblastoma through inhibiting STAT3 signaling. Citation Format: Hui Xiao, Wenying Yu, Veronica R. Olson, Chenglong Li, Peter Houghton, Jiayuh Lin. A novel small molecule, LY5, selectively inhibits STAT3 phosphorylation and activities and exhibits potent growth suppressive activity in cancer cells. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3252. doi:10.1158/1538-7445.AM2013-3252