Abstract 5119: Smac mimetic inhibits tumorigenicity and growth of glioblastoma by promoting differentiation of glioblastoma cancer stem-like cells

Abstract

Abstract Inhibitors of apoptosis (IAP) proteins are often overexpressed in human cancers including glioblastoma (GBM) and are well characterized for their antiapoptotic properties. Recently, a broader role of IAP proteins in tumor biology has been described, as they also regulate several non-apoptotic signal transduction pathways. Therefore, we investigated the effect of non-toxic concentrations of small-molecule Smac mimetics, which antagonize IAP proteins, on differentiation of cancer stem-like cells (CSLCs) derived from primary GBM specimens. Since CSLCs have been implicated in resistance to chemo- and radiotherapy and tumor recurrence, they are considered as critical therapeutic targets in GBM. Here, we identify a novel function of Smac mimetic in regulating differentiation of GBM CSLCs by activating NF-κB. Smac mimetic at non-lethal doses stimulates morphological changes associated with differentiation of GBM CSLCs. Smac mimetic increases transcriptional activity, mRNA and protein levels of the astrocytic marker GFAP without altering expression of the neuronal marker β-III-tubulin, indicating that Smac mimetic induces astrocytic differentiation of GBM CSLCs. Molecular studies reveal that Smac mimetic triggers processing of the NF-κB subunit p100 to p52, nuclear translocation of p52 and p50 and increased NF-κB DNA-binding. Intriguingly, inhibition of NF-κB by overexpression of dominant-negative IκBα superrepressor (IκBα-SR) blocks the Smac mimetic-stimulated increase in GFAP and differentiation. Interestingly, this Smac mimetic-stimulated differentiation is associated with reduced expression of stemness markers such as CD133, Nanog and Sox2 in GBM CSLCs. In contrast, Smac mimetic does not alter cell morphology, differentiation and expression of stemness markers in non-malignant neural stem cells. Importantly, Smac mimetic treatment reduces clonogenicity of GBM CSLCs in vitro and in vivo, suppresses their tumorigenicity in orthotopic and subcutaneous mouse models of GBM and significantly increases the survival of mice bearing GBM. By identifying a novel role of Smac mimetic in promoting the differentiation of GBM CSLCs, these findings provide new insights into Smac mimetic-regulated non-apoptotic functions with important implications for targeting GBM CSLCs. Citation Format: Aurelie Tchoghandjian, Claudia Jennewein, Ines Eckhardt, Stefan Momma, Dominique Figarella-Branger, Simone Fulda. Smac mimetic inhibits tumorigenicity and growth of glioblastoma by promoting differentiation of glioblastoma cancer stem-like cells. [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 5119. doi:10.1158/1538-7445.AM2014-5119