FoxO3a induces temozolomide resistance in glioblastoma cells via the regulation of β-catenin nuclear accumulation

Abstract

Glioblastoma multiforme (GBM), the most common malignant brain tumor, is currently treated with temozolomide (TMZ), but GBM often exhibits resistance to TMZ. Although several mechanisms underlying GBM resistance to TMZ have been identified, these mechanisms are yet to fully explain how GBM gains resistance to TMZ. Our previous work has shown that FoxO3a, a member of the FoxO subfamily of transcription factors, promotes glioma cell proliferation and invasion. In this study, we sought to determine whether FoxO3a participates in TMZ resistance in GBM cells. Parental cell lines (also designated as sensitive cell lines) U87-MG and U251-MG, as well as the corresponding resistant cell lines U87-TR and U251-TR (generated by repeated TMZ treatments), were subjected to western blot analysis. Our results showed that the resistant cells (both U87-TRand U251-TR) exhibited higher levels of FoxO3a and β-catenin relative to their corresponding sensitive counterparts. Depletion of FoxO3a in the resistant cells enhanced the cytotoxic effect of TMZ. Further investigation showed that FoxO3a depletion did not affect the total protein level of β-catenin, but otherwise markedly reduced the nuclear β-catenin level. Taken together, these findings strongly support that FoxO3a renders GBM cells resistant to TMZ treatment, at least in part, through the regulation of β-catenin nuclear accumulation.

Repaglinide Silences the FOXO3/Lumican Axis and Represses the Associated Metastatic Potential of Neuronal Cancer Cells

“…The oncogenic properties of the transcription factor FOXO3 have been reported in different cancers [2][3][4][5][6][7][8][9][10]. In high-stage NB, FOXO3 promotes tumor angiogenesis in vivo [11] and chemoprotection in vitro [12].…”

“…In high-stage NB, therapy-failure due to acquired chemoresistance and metastasis formation results in a high relapse rate and a five year survival probability of less than 40% [1]. The transcription factor FOXO3, a member of the forkhead box O (FOXO) superfamily, has been associated with elevated tumorigenicity in different cancers [2][3][4][5][6][7][8][9][10]. In concordance, our own Preparation of protein extracts of SH-EP/FOXO3 cells incubated with 75 nM 4OHT for 8 and 16 h was done as described previously [32].…”

Towards Targeting PI3K-Dependent Regulation of Gene Expression in Brain Cancer

“…FOXO-mediated inhibition of cell proliferation has led to the view that these factors have tumor suppressive roles [41], although this view may be too simplistic given what appears to be opposing FOXO function in glioma. A recent study examining FOXO3a expression in patient HGGs suggests a strong association between high expression and poor prognosis [42], while another study using two human GBM cell lines demonstrated that FOXO3a expression induces TMZ resistance [43]. These recent studies in GBM patients and cells, underscore the importance of FOXO in supporting brain cancer cell growth and survival and highlight the potential therapeutic importance of the FOXO transcription factors in HGG.…”

A drug library screen identifies Carbenoxolone as novel FOXO inhibitor that overcomes FOXO3-mediated chemoprotection in high-stage neuroblastoma

“…FOXO3 has been characterized as tumor suppressor gene based on its anti-proliferative and pro-apoptotic functions [2]. However, an increasing number of studies point out the "dark side" of FOXO3 and describe its potential oncogenic properties in different cancer types, including chronic myeloid leukemia (CML), acute myeloid leukemia (AML), breast cancer, glioblastoma, and pancreatic cancer [4][5][6][7][8][9][10][11][12][13][14][15][16][17]. Our own studies demonstrate that nuclear FOXO3 promotes tumor angiogenesis in vivo [18] and chemoresistance in vitro [19] in aggressive NB.…”

“…Sykes et al observed active FOXO3 in AML patient samples and demonstrated that conditional deletion of FOXOs in an AML mouse model reduces leukemia-initiating cell function in vivo, improves animal survival, and mediates myeloid maturation and AML cell death [12]. Recent studies indicate that FOXO3 triggers chemoresistance in glioblastoma via the regulation of β-catenin [16] and elevated FOXO3 expression is associated with poor patient prognosis [17]. Yu et al identified FOXO3 as a key regulator in cetuximab resistance in metastatic colorectal cancer [25].…”