Abstract 4400: Blockade of Her2 binding to Hsp90 by emodin azide methyl anthraquinone derivative induces proteasomal degradation of Her2

Abstract

Abstract Overexpression of HER2/neu, a transmembrane tyrosine kinase acting as a coreceptor for other EGFR family members, is well known to be associated with a poor prognosis in cancer. In the present study, we observed that emodin AMAD, a novel emodin azide methyl anthraquinone derivative, extracted from the nature giant knotweed rhizome of traditional Chinese herbs, potently decreased Her2/neu protein in dose- and time-dependent manners and also inhibited the downstream MAPK and PI3K-Akt signaling pathway. Intriguingly, reserve transcription-PCR and protein turn-over assay revealed that the decrease of Her2/neu was independent of mRNA level but primarily owing to its protein stability. Meanwhile, proteasome inhibitor MG132 but not lysosome inhibitor chloroquine could restore Her2/neu and polyubiquitination of Her2/neu was augmented during emodin AMAD treatment. Furthermore, immunofluorescence study with anti-Her2/neu antibody showed that emodin AMAD disturbed the subcellular distribution of Her2/neu, with decreased location in the plasma membrane. Importantly, coimmunoprecipitation with anti-Hsp90 antibody revealed that emodin AMAD markedly impaired the binding between Hsp90 and Her2/neu. In addition, combination of emodin AMAD treatment and SiRNA against Her2 synergistically inhibited proliferation and induced apoptosis. Taken together, these data suggest that blockade of Her2/neu binding to Hsp90 and following proteasomal degradation of Her2/neu was involved in emodin AMAD-induced apoptosis in Her2/neu-overexpressing cancer cells. Our results provide suggestions that emodin AMAD could be promising as a new targeting therapeutic strategy in the treatment of Her2/neu-overexpressing cancers. 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 4400. doi:10.1158/1538-7445.AM2011-4400