Arsenic trioxide inhibits glioma cell growth through induction of telomerase displacement and telomere dysfunction

Abstract

Glioblastomas are resistant to many kinds of treatment, including chemotherapy, radiation and other adjuvant therapies. As₂O₃ reportedly induces ROS generation in cells, suggesting it may be able to induce telomerase suppression and telomere dysfunction in glioblastoma cells. We show here that As₂O₃ induces ROS generation as well as telomerase phosphorylation in U87, U251, SHG4 and C6 glioma cells. It also induces translocation of telomerase from the nucleus to the cytoplasm, thereby decreasing total telomerase activity. These effects of As₂O₃ trigger an extensive DNA damage response at the telomere, which includes up-regulation of ATM, ATR, 53BP1, γ-H₂AX and Mer11, in parallel with telomere fusion and 3′-overhang degradation. This ultimately results in induction of p53- and p21-mediated cell apoptosis, G2/M cell cycle arrest and cellular senescence. These results provide new insight into the antitumor effects of As₂O₃ and can perhaps contribute to solving the problem of glioblastoma treatment resistance.