Abstract B48: Aurora kinase A plays a central role in the differentiation, survival, and self-renewal of human neuroblastoma SK-N-BE(2)-derived cancer stem cells

Abstract

Abstract Aurora kinase A is upregulated in numerous types of cancers. Since this protein is involved in mitotic spindle formation and cell cycle progression, its dysregulation leads to aberrant chromosomal segregation and consequent aneuploidy. It has been clarified that Aurora A is a key player in neuroblastoma because of its ability to protect the oncogene product N-myc from degradation, and the over-expression of the two of them represents a negative prognostic factor. Neuroblastoma usually develops in children and, up to the present time, the available pharmacological therapies have proven inadequate to treat the MYCN amplified sub-type of cancer, which is the most aggressive and malignant form of the tumor. Therefore, there is an urgency to develop new strategies that will improve its treatment. A novel approach to contrast cancer development and relapse is to target the subpopulation of the tumor initiating cells (or cancer stem cells), due to their multi-drug resistance and self-renewal abilities. In this study, we have employed the SK-N-BE(2) cell line as an in vitro human neuroblastoma model, and compared the effects of Aurora A inhibition on the whole population (WP) and on the derived neurospheres (NS) obtained by their continuous growth in selective medium. We tested the effects of both a specific Aurora A inhibitor, ENMD-2076, and a pan-Aurora isoforms blocker, VX-680, for their influence over cellular physiology, morphology and signaling. The specificity of the results was confirmed by the use of a validated Aurora A siRNA. In SK-N-BE(2) WP and NS, our findings confirmed the ability of Aurora A to protect N-myc from degradation. Moreover, the isolation and characterization by FACS, confocal microscopy and immunoblotting of an aldehyde dehydrogenase-positive side population, confirmed the presence of a fraction of cells with self-renewal capabilities and stem-like properties. The analysis of the signaling network of Aurora A showed functional relationships with the transcription factor STAT3, which is associated with neuronal survival and differentiation, after IL-6 challenge. Furthermore, either Aurora A pharmacological block or silencing induced the phosphorylation of the microtubule associated protein 2 (map2) specifically in the NS, an event that maintains the microtubule in a dynamic state, which is a prerequisite for neurite outgrowth. Our results suggest that Aurora A represents an amenable target for the treatment of neuroblastoma, and gives new insights into its role in regulating neuronal plasticity and differentiation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr B48.