Abstract 508: Signal transduction and activator of transcription (STAT) 3 is necessary for environment-mediated drug resistance

Abstract

Abstract There is recent evidence that STAT3 plays a pivotal and central role in controlling inflammatory pathways that promote malignant transformation and progression, including the ability of tumor cells to escape drug-induced apoptosis. Using neuroblastoma as a model, our laboratory had previously demonstrated that bone marrow mesenchymal stem cells through their production of interleukin-6 are a source of environment-mediated drug resistance. Here we have examined the role of STAT3, a downstream target of IL-6, in this effect. We first demonstrate that in contrast to many other cancers, STAT3 is not constitutively active in most neuroblastoma cells. However, it is rapidly phosphorylated after 15 minutes of exposure to IL-6 and its soluble receptor (sIL6-R). Activation of STAT3 is associated with its nuclear translocation and DNA binding. Treatment of CHLA-255 and SK-N-SH neuroblastoma cells with IL-6 increases their resistance to Etoposide and Melphalan in a dose-dependent manner. IL-6 inhibits the release of cytochrome C from the mitochondria and upregulates several pro-survival factors like Bcl-XL, XIAP and survivin without affecting the expression of Bax and Bad. The protective effect of IL-6 on drug-induced apoptosis is significantly inhibited in the presence of the STAT3 inhibitor Stattic (2.5 μM) or upon downregulation of STAT3 by siRNA, indicating that STAT3 is necessary for drug resistance. We also show that sIL-6R, produced by monocytes, enhances STAT3 activation and promotes drug resistance. In vivo, IL-6 and sIL-6R increase STAT3 activation in CHLA-255 neuroblastoma cells and their proliferation. Finally we observed elevated expression of phosphoSTAT3 in bone marrow samples of patients with metastatic neuroblastoma cells. Altogether, the data demonstrate that in neuroblastoma STAT3 activation by IL-6 in the tumor microenvironment plays a key role in environment-mediated drug resistance. 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 508. doi:10.1158/1538-7445.AM2011-508