Abstract
Abstract Glioblastoma multiforme (GBM) is a lethal brain cancer with a life expectancy of only 12-15 months. Current standard treatment for GBM is surgery and chemoradiation. However, there are many difficulties when it comes to treating this aggressive brain cancer due to the inherent radio- and chemo-resistance. Consequently, there is a critical need for new therapeutic approaches to make radiation/chemotherapy more effective. Ataxia telangiectasia (A-T) patients are extremely sensitive to ionizing radiation. The protein mutated in A-T, ATM (A-T mutated), controls the cells’ response to radiation, referred to as the DNA damage response (DDR). ATM is a master protein kinase that targets many proteins during the DDR including regulators of cell cycle checkpoints, DNA repair, and apoptosis. In addition, without any radiation, ATM might regulate glioma dispersal. Using a highly specific inhibitor of the ATM kinase (ATMi), we recently showed that ATM regulates both the ERK and AKT signaling pathways and controls glioma cell migration and invasion in vitro. To take these studies further we have now used a genetic approach and knocked down ATM in human glioma cells. We have recapitulated our previous finding with an ATMi and shown that ATM knockdown glioma cells have reduced ability to migrate in vitro. In order to determine whether MEK/ERK and/or AKT regulate migration, human glioma cells were exposed to a MEK (PD0325901) or an AKT (MK-2266) inhibitor in a ‘scratch-assay’. We found that only the former compound affected migration in vitro. Hence, we have shown that ATM regulates glioma migration in vitro, perhaps via MEK/ERK. On the other hand, ATM might regulate invasion via AKT. The signaling relationship in vitro between ATM, ERK, and AKT is currently being investigated. Furthermore, ongoing studies will establish whether ERK and AKT signaling affect migration and invasion in vivo. Citation Format: Jasmine L. Allen, Allison F. Wagner, Jason M. Beckta, James Watson, Sarah E. Golding, Kristoffer C. Valerie. ATM regulates glioma migration via MEK-ERK not AKT. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 437. doi:10.1158/1538-7445.AM2013-437 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.
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