Abstract 250: The critical requirement of ATM function in PTEN null cell lines

Introduction: The tumour suppressor PTEN is frequently lost in multiple cancer types, loss of PTEN function has been linked to activation of the AKT signalling pathway. The regulation of the AKT signalling has long been attributed as the key tumour suppressing function of PTEN. However, it has recently been demonstrated that PTEN null cells demonstrate genomic instability and require base excision repair (BER) for survival. One of the critical functions of BER is the repair of oxidative DNA damage; we postulated that PTEN might have a role in the maintenance of this form of damage. Additionally, we investigated which molecular pathways were involved in the response of this form of DNA damage in PTEN null cells. Results: Using isogenic cell lines we found an increased in baseline ROS levels according to PTEN status. Specifically the increase in ROS levels was correlated to an increase in the levels of double strand breaks as measured by levels of activated γH2AX, formation of γH2AX foci and activation of the DNA damage response kinase ATM. Furthermore, inhibition of ATM function both via siRNA knockdown and small molecule inhibition in PTEN null cells resulted in cell cycle arrest followed by apoptosis. Strikingly this dependence on ATM activity was independent of AKT activity, suggesting that the oxidative DNA damage was the result of a loss in PTEN function independent of its role in the regulation of the AKT activation. Conclusions: These observations suggest that PTEN may play a role in the maintenance of the repair of ROS DNA damage; furthermore it maybe postulated that inhibition of ATM maybe a suitable therapeutic intervention for PTEN null tumours. 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 250. doi:10.1158/1538-7445.AM2011-250