Differential Response of Glioma Cells to FOXO1-Directed Therapy

Abstract

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 Aktindependent phosphorylation of FOXO1 at S249. A cyclindependent 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]

Fenofibrate induces G0/G1 phase arrest by modulating the PPARα/FoxO1/p27kip pathway in human glioblastoma cells

“…The FoxO proteins (FoxO1, FoxO3a, FoxO4, and FoxO6) are key effectors of PI3K/Akt signaling and regulate many biological processes such as cell cycle progression and cell differentiation [16,26]. In addition, as a transcription factor, FoxO1 acts at a convergence point of several growth factor receptor tyrosine kinase pathways that may play central roles in glioma tumorigenesis [16,17]. In a previous study, Chen et al found that FF-induced lipid-lowering effects were associated with increased expression of FoxO1 in myotubes [27].…”

“…Moreover, as a substrate of Akt, FoxO1 plays a causal role in tumor suppression and results in the transcriptional activation of p27 kip [15,16]. A recent study has shown that targeting FoxO1 could effectively induce glioma cell death and inhibit tumor growth by controlling the expression of cell cycle-related genes [17].…”

Caffeine-induced nuclear translocation of FoxO1 triggers Bim-mediated apoptosis in human glioblastoma cells

“…FoxO1 has emerged as an important effector arm of PI3K/Akt signaling that regulates multiple biological processes, such as cell differentiation and apoptosis [23]. In addition, as a transcription factor, FoxO1 acts at a convergence point of several growth factor receptor tyrosine kinase pathways and may thus play an important role in glioma tumorigenesis [30]. In the present study, we have shown that caffeine not only increases the expression of both FoxO1 and its proapoptotic target Bim but also promotes nuclear translocation of FoxO1 in U251 cells undergoing apoptosis.…”

Effect of BMI1 Knockdown on Cell Proliferation, Apoptosis, Invasiveness, and Migration of U251 Glioma Cells

“…Phosphorylated Akt promotes cell survival, proliferation, and possibly other malignant properties such as motility and invasiveness by phosphorylating downstream targets such as anti-apoptotic protein Bax and forkhead box protein (FOXO) transcriptional factors [34,35]. The FOXO factors function as transcriptional activators and their activation regulates apoptotic responses, cell cycle arrest, and detoxification of reactive oxygen species as well as repair of damaged DNA [36][37][38]. Here, we did not study the role of BMI1 in the regulation of the Akt pathway.…”