FoxO3a Functions as a Key Integrator of Cellular Signals That Control Glioblastoma Stem-like Cell Differentiation and Tumorigenicity

Abstract

Glioblastoma is one of the most aggressive types of human cancer, with invariable and fatal recurrence even after multimodal intervention, for which cancer stem-like cells (CSLCs) are now being held responsible. Our recent findings indicated that combinational inhibition of phosphoinositide-3-kinase/Akt/mammalian target of rapamycin (mTOR) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)/extracellular signalregulated kinase (ERK) pathways effectively promotes the commitment of glioblastoma CSLCs to differentiation and thereby suppresses their tumorigenicity. However, the mechanism by which these two signaling pathways are coordinated to regulate differentiation and tumorigenicity remains unknown. Here, we identified FoxO3a, a common phosphorylation target for Akt and ERK, as a key transcription factor that integrates the signals from these pathways. Combinational blockade of both the pathways caused nuclear accumulation and activation of FoxO3a more efficiently than blockade of either alone, and promoted differentiation of glioblastoma CSLCs in a FoxO3a expression-dependent manner. Furthermore, the expression of a constitutively active FoxO3a mutant lacking phosphorylation sites for both Akt and ERK was sufficient to induce differentiation and reduce tumorigenicity of glioblastoma CSLCs. These findings suggest that FoxO3a may play a pivotal role in the control of differentiation and tumorigenicity of glioblastoma CSLCs by the PI3K/Akt/ mTOR and MEK/ERK signaling pathways, and also imply that developing methods targeting effective FoxO3a activation could be a potential approach to the treatment of glioblastoma.

Prolyl hydroxylation by EglN2 destabilizes FOXO3a by blocking its interaction with the USP9x deubiquitinase

“…Somatic deletion of all three FOXOs (FOXO1, FOXO3, and FOXO4) engenders a cancer-prone condition in mice, further strengthening its tumor suppressor role in vivo (Paik et al 2007). Consistent with this, decreased expression of FOXO3a associated with poor outcomes in breast cancer and neuroblastoma (Sunayama et al 2011;Jiang et al 2013;Santo et al 2013). Conversely, FOXO3a nuclear localization is associated with good prognosis in luminal-like breast cancer (Habashy et al 2011).…”

Inactivation of AKT, ERK and NF-κB by genistein derivative, 7-difluoromethoxyl-5,4′-di-n-octylygenistein, reduces ovarian carcinoma oncogenicity

“…To integrate the abovementioned tight association of FoxO3a with OVCSLC oncogenicity inhibition related to AKT and/or ERK and/or NF-κB pathway suppression, our data showed that reduced OVCSLC oncogenicity in vitro due to the suppressive effects of DFOG on AKT and/or ERK and/or NF-κB pathways requires FoxO3a expression. These results support the viewpoint of Sunayama et al (1) that FoxO3a likely has an important function in controlling CSLCs via PI3K/AKT/mTOR and MEK/ERK signaling, thereby implying that tools effectively targeting FoxO3a induction may constitute a viable option for human carcinoma treatment.…”

“…Since the FoxO3a function is closely associated with OVCSLC oncogenicity inhibition related to suppressed AKT and/or ERK and/or NF-κB pathway (1,24,25), whether oncogenicity reduction by DFOG in vitro depended on FoxO3a expression in OVCSLCs from SKOV3 cells was assessed. Fig.…”

FoxO3a and disease progression

“…Among the FoxO family, FoxO3a has been shown to be deregulated in several tumor types, including breast cancer [83][84][85] , prostate cancer [86][87][88] , glioblastoma [89] and leukemia [90,91] . Therefore, FoxO3a has been targeted as a way to treat several types of cancers.…”