FBW7 is associated with prognosis, inhibits malignancies and enhances temozolomide sensitivity in glioblastoma cells

Abstract

F-box and WD repeat domain-containing 7(FBW7) is a SCF-type E3 ubiquitin ligase targeting a multitude of oncoproteins for degradation. Acting as one of the most important tumor suppressor it is frequently inactivated in various tumors. In this study we aimed to evaluate the relationship of FBW7 with glioma pathology and prognosis, and examine its effect in glioma malignancies and temozolomide(TMZ)-based therapy. Clinical tissues and TCGA database analysis revealed FBW7 expression was correlated inversely with glioma histology and positively with patient survival time. Lentivirus transfection- induced FBW7 overexpression significantly suppressed proliferation, invasion and migration of U251 and U373 cells whereas knockdown of FBW7 by targeted shRNA promoted proliferation, invasion and migration of glioma cells. Most importantly, the expression level of FBW7 was found to affect 50% inhibition concentration(IC50) of U251 and the TMZ resistant variant. Combining TMZ with FBW7 overexpression notably increased the cytotoxicity than TMZ treatment alone, which was conversely attenuated by FBW7 knockdown. Moreover, flow cytometry(FC) analysis showed either overexpression of FBW7, TMZ or the combination increased proportion of G2/M arrest and apoptotic rate whereas FBW7 inhibition reduced G2/M arrest and apoptosis in U251 cells. Finally, mechanistic study found FBW7 overexpression downregulated Aurora B, Mcl1 and Notch1 levels in a time-dependent pattern and this expressional suppression was independent of TMZ. These findings collectively demonstrate the critical role of FBW7 as a prognostic factor and a potential target to overcome chemoresistance of glioblastoma.

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