Abstract LB-164: Aurora Kinase A as a target for sensitizing glioma cells to radiation treatment

Abstract

Abstract Purpose: Eukaryotic cells have a complex cell cycle process that is regulated by many factors. Tumors arise when cell cycle progression is deregulated. Mitosis is a well coordinated event and occurs only when proper signals allow the cell cycle machinery to proceed beyond the G2/M checkpoint. Aurora kinase A (AurKA) is a mitotic regulator involved in bipolar-spindle assembly and chromosome segregation, and also recruits other proteins and cofactors that are important for mitotic events. AurKA is upregulated in many cancers and has been shown to cause aneuploidy and induce oncogenic transformation. AurKA overexpression allows cells to surpass the G2/M checkpoint and enter mitosis prematurely, which leads to chromosomal abnormalities and genomic instability. Experimental Design: Here we are investigating AurKA in established (ATCC) and primary glioblastoma (GBM) cell lines. Assays measuring radiosensitivity were conducted using wild-type and AurKA knockdown GBM cells. These include the clonogenic survival assay, MTS proliferation assay, cell-cycle analysis, and Annexin V apoptosis assay. Protein profiles were used to investigate pro-apoptotic, anti-apoptotic, and other downstream and upstream signaling pathways after radiation treatment. Results and Discussion: Irradiation induces AurKA expression in both our established and primary GBM cell lines. Next we silenced AurKA using lentiviral mediated shRNA transduction. AurKA knockdown cells exhibit greater radiosensitivity when compared to cells transduced with a mock vector. AurKA and p53 interact at multiple levels. Preclinical data with AurKA inhibitors suggest p53-negative tumors may be more sensitive to AurKA inhibitors than p53-positive tumors. To investigate which subset of GBMs show greater response to AurKA silencing, we will conduct experiments using our panel of isogenic GBM cells lines. Our hypothesis is that AurKA knockdown cells will show reduced proliferation and increased apoptosis, thereby leading to cell death. The outcome of this preclinical study would be to evaluate AurKA as a potential therapeutic target for the treatment of GBM. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr LB-164.