Abstract 1983: A cell-permeable Stat3 SH2 domain mimetic inhibitor of Stat3 activation inhibits growth of human breast tumor xenografts

Abstract

Abstract Human tumors harbor multiple molecular aberrations that have become the driving force for uncontrolled cell proliferation and survival, and other tumor-associated processes. Constitutive activation of the Signal Transducer and Activator of Transcription (Stat) 3 protein is a frequent occurrence in many human cancers, including breast cancer. Given the role of aberrant Stat3 activity in human tumors, small-molecule Stat3 inhibitors would be useful novel therapeutics and tools for probing Stat3-mediated tumor processes. We herein report that a 28-mer peptide, SPI, composed of the amino acid residues 588-615 of the Stat3 SH2 domain, replicates Stat3 biochemical properties and functions as a Stat3 inhibitor. Studies show SPI and Stat3 (or Stat3 SH2 domain) both bind with similar affinities to known Stat3-binding phosphotyrosine (pY) peptide motifs, including the epidermal growth factor receptor (EGFR) peptides, pY1068EGFR and pY1086EGFR, and the high-affinity, interleukin-6 receptor (IL-6R)/gp130-derived peptide, GpYLPQTV-NH2. Consequently, SPI potently and selectively inhibits Stat3 SH2 domain:pY interactions and disrupts the binding of Stat3 to the IL-6R/gp130 peptide, GpYLPQTV-NH2. Fluorescence imaging studies show SPI is cell membrane-permeable. Treatment with SPI of malignant cells that harbor aberrant Stat3 activity resulted in the selective inhibition of constitutive Stat3 phosphorylation, and of Stat3 DNA-binding and transcriptional activities. By contrast, similar treatments have little or no effects on the induction of the Stat1, Stat5, and Erk1/2MAPK pathways in malignant cells or in EGF-stimulated fibroblasts. In contrast to normal cells, human breast, pancreatic, prostate, and non-small cell lung cancer cells harboring constitutively-active Stat3 are highly sensitive to SPI and undergo extensive morphology changes, concomitant with the loss of viability and apoptosis. Significantly, treatment with SPI or its inverse sequence version strongly inhibited the growth of human breast tumor xenografts in mice, which is associated with the down-regulation of the expression of the known Stat3-regulated genes, Cyclin D1, Bcl-xL and Survivin. Our study identifies SPI as a novel molecular probe for interrogating Stat3 signaling and that functions as a selective Stat3 inhibitor, which induces antitumor response in vivo. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1983. doi:10.1158/1538-7445.AM2011-1983