Abstract 3802: Withacnistin blocks binding of STAT3 and STAT5 to growth factor and cytokine receptors and induces regression of breast tumors in vivo

Abstract

Abstract The binding of STAT3 and STAT5 to growth factor and cytokine receptors such as EGFR and the IL-6 receptor gp130 is critical to their activation and ability to contribute to malignant transformation. Therefore, interfering with these biochemical processes could lead to the discovery of novel anti-cancer agents. In this manuscript, we show that the natural product, Withacnistin (Wit) blocks EGF- and IL-6-stimulated binding of STAT3 and STAT5 to EGFR and gp130. Furthermore, Wit inhibits EGF-, PDGF-, IL-6-, IFNβ- and GM-CSF-stimulation of tyrosine phosphorylation of STAT3 and STAT5 but not of EGFR or PDGFR. The inhibition of P-STAT3 and P-STAT5 occurred very rapidly, within minutes of Wit treatment and growth factor stimulation. Wit also inhibits STAT3 nuclear translocation, DNA binding, promoter transcriptional activation, and it suppresses the expression levels of STAT3 target genes such as Bcl-xL and Mcl-1. Finally, Wit induces apoptosis, inhibits anchorage-independent growth and invasion, and causes breast tumor regression in an ErbB2-driven transgenic mouse model. These data warrant further development of Wit as a novel anti-cancer drug for targeting tumors that harbor hyperactivated STAT3 and STAT5. Citation Format: Xiaolei Zhang, Michelle A. Blaskovich, Kara D. Forinash, Said M. Sebti. Withacnistin blocks binding of STAT3 and STAT5 to growth factor and cytokine receptors and induces regression of breast tumors in vivo. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3802. doi:10.1158/1538-7445.AM2014-3802