Copper induces cellular senescence in human glioblastoma multiforme cells through downregulation of Bmi-1

Most human tumor cells, including glioblastoma multiforme (GBM) cells, have aberrant control of cell aging and apoptosis. Subcytotoxic concentrations of oxidative or stress-causing agents, such as hydrogen peroxide, may induce human cell senescence. Thus, induction of tumor cells into premature senescence may provide a useful in vitro model for developing novel therapeutic strategy to combat tumors. In the present study, we assessed the molecular mechanism(s) underlying senescence in GBM cells induced by copper sulfate. Following pretreatment with subcytotoxic concentrations of copper sulfate, U87-MG tumor cells showed typical aging characteristics, including reduced cell proliferation, cell enlargement, increased level of senescence-associated (beta-galactosidase (SA beta-gal) activity, and overexpression of several senescence-associated genes, p16, p21, transforming Growth factor (beta-1 (TGF-beta 1), insulin growth factor binding protein 3 (IGFBP3) and apolipoprotein J (ApoJ). We further demonstrated that the Bmi-1 pathway was downregulated in GBM cells in parallel with the induced senescence. The present study for the first time demonstrates the ability of copper to induce GBM cell senescence by downregulating Bmi-1.