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

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.