This Article Full Text Full Text (PDF) Supplementary Data All Versions of this Article: 0008-5472.CAN-08-4540v1 69/13/5433    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Lau, C. J. Articles by Nalbantoglu, J. PubMed PubMed Citation Articles by Lau, C. J. Articles by Nalbantoglu, J.

Differential Response of Glioma Cells to FOXO1-Directed Therapy

Departments of ¹ Experimental Medicine, ² Neurology and Neurosurgery, McGill University; ³ Montreal Neurological Institute, Montreal, Quebec, Canada

Requests for reprints: Josephine Nalbantoglu, Montreal Neurological Institute, 3801 University Street, Montreal, Quebec, Canada H3A 2B4. Phone: 514-398-8534; Fax: 514-398-7371; E-mail: josephine.nalbantoglu{at}mcgill.ca.

Key Words: FOXO1 • glioma • xenograft • adenovirus • cyclin-dependent kinase

Gliomas are the most common adult primary brain tumors, and the most malignant form, glioblastoma multiforme, is invariably fatal. The phosphatidylinositol 3-kinase (PI3K)-Akt signaling pathway is altered in most glioblastoma multiforme. PTEN, an important negative regulator of the PI3K-Akt pathway, is also commonly mutated in glioma, leading to constitutive activation of Akt. One ultimate consequence is phosphorylation and inactivation of FOXO forkhead transcription factors that regulate genes involved in apoptosis, cell cycle arrest, nutrient availability, DNA repair, stress, and angiogenesis. We tested the ability of a mutant FOXO1 factor that is not subject to Akt phosphorylation to overcome dysregulated PI3K-Akt signaling in two PTEN-null glioma cell lines, U87 and U251. Adenovirus-mediated gene transfer of the mutant FOXO1 successfully restored cell cycle arrest and induced cell death in vitro and prolonged survival in vivo in xenograft models of human glioma (33% survival at 1 year of animals bearing U251 tumors). However, U87 were much more resistant than U251 to mutant FOXO1-induced death, showing evidence of increased nuclear export and Akt-independent phosphorylation of FOXO1 at S249. A cyclin-dependent kinase 2 inhibitor decreased phosphorylation of S249 and rendered U87 cells significantly more susceptible to mutant FOXO1-induced death. Our results indicate that targeting FOXO1, which is at the convergence point of several growth factor receptor tyrosine kinase pathways, can effectively induce glioma cell death and inhibit tumor growth. They also highlight the importance of Akt-independent phosphorylation events in the nuclear export of FOXO1. [Cancer Res 2009;69(13):5433–40]