Abstract 2609: The role of focal adhesion kinase (FAK), PI3K/AKT and p53/mouse double minute 2 homologue (MDM2) complex in the pathobiology of Merlin-deficient tumors

Abstract

Abstract Deficiency of the tumor suppressor merlin leads to the development of schwannomas, meningiomas and ependymomas occurring spontaneously or as a part of a hereditary disease Neurofibromatosis type 2 (NF2). Another tumor suppressor/transcription factor p53 regulates proliferation, survival and differentiation. P53 deficiency/inactivation correlates with tumor development and can be negatively regulated by FAK, PI3K/AKT and MDM2 and possibly positively by merlin and JNK in different models. The function of p53 in merlin deficient tumors is not known. Using our in vitro model of primary human schwannoma cells we demonstrated that FAK is overexpressed/activated and localises to the nucleus in schwannoma cells leading to increased proliferation. AKT is strongly activated via PDGF- and IGF-I- receptors increasing survival. Here we investigated p53 regulation and its role in proliferation and survival of human primary schwannoma cells. p53 is downregulated and MDM2 upregulated in human schwannoma cells leading to increased proliferation and survival. p53 is regulated by merlin involving JNK FAK, AKT and MDM2. Thus merlin potentiates p53 activity and when using Nutlin-3 this increases p53 stability and total levels of p53 in schwannoma cells decreasing proliferation and survival. These findings are important to dissect mechanisms responsible for development of merlin-deficient tumors and identification of therapeutic targets. Citation Format: Clemens O. Hanemann, Sylwia Ammoun, Marei C. Schmid, Lu Zhou. The role of focal adhesion kinase (FAK), PI3K/AKT and p53/mouse double minute 2 homologue (MDM2) complex in the pathobiology of Merlin-deficient tumors. [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 2609. doi:10.1158/1538-7445.AM2014-2609