Abstract 3348: Netrin-4/Integrin Beta-4 Interaction Promotes Glioblastoma Cell Proliferation and Protects from Temozolomide Induced Cellular Senescence Via Activating PI3K/AKT Pathway

Abstract Netrin-4 (NTN4) is a secreted laminin-related protein, which was originally observed to guide neuronal axons during neuronal development. Recently, it has been found to be expressed in many other tissues and tumor types, and to contribute to the regulation of cell adhesion, migration, proliferation, and apoptosis. Glioblastoma multiforme (GBM) is the most common primary tumor of central nervous system (CNS). Although there is no remedy for this fatal disease, the efficacy of temozolomide (TMZ) -an orally taken alkylating agent- has been demonstrated in the treatment of glioblastoma. However, the sensitivity of GBM cells to TMZ is interfered by many factors such as MGMT expression, AKT activation, etc. Here we have explored the functions and molecular mechanisms of NTN4 in GBM. The suppression of NTN4 expression in GBM cell lines significantly reduced cell proliferation and motility and increased serum deprivation-induced apoptosis. By using tandem affinity purification and mass spectrometric analysis, we identified the physical interaction between integrin beta-4 (ITGB4) and NTN4. This interaction mediates AKT phosphorylation and concomitant mitogenic effects. Furthermore, silencing either NTN4 or ITGB4 in GBM cell induced cellular senescence. Temozolomide induces cellular senescence in MGMT devoid glioma cell lines. Addition of exogenous recombinant NTN4 protein rescued TMZ induced senescence and AKT dephosphorylation in GBM cells in an ITGB4 dependent manner. Current data suggest that the NTN4-ITGB4 interaction promotes GBM cell proliferation and protects GBM cell from TMZ triggered cellular senescence via activating PI3K/AKT pathway. Citation Format: Yizhou Hu, Irene Ylivinkka, Li Li, Ping Chen, Sampsa Hautaniemi, Tuula A. Nyman, Jorma Keski-Oja Keski-Oja, Marko Hyytiäinen. Netrin-4/Integrin beta-4 interaction promotes glioblastoma cell proliferation and protects from temozolomide induced cellular senescence via activating PI3K/AKT pathway. [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 3348. doi:10.1158/1538-7445.AM2014-3348