title: 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.
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, P. R. China.
authors.forename: Ye
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, P. R. China.
authors.forename: Yunqian
authors.initials: Y
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, P. R. China.
authors.forename: Chengyuan
authors.initials: C
authors.lastname: Ma
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, P. R. China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, P. R. China.
authors.forename: Haiyang
authors.initials: H
authors.lastname: Xu
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, P. R. China.
authors.forename: Hongquan
authors.initials: H
authors.lastname: Yu
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, P. R. China.
authors.forename: Songbai
authors.initials: S
authors.lastname: Xu
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, P. R. China.
authors.forename: Qingchun
authors.initials: Q
authors.lastname: Mu
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, P. R. China.
authors.forename: Haisong
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, P. R. China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, First Hospital of Jilin University, Changchun, P. R. China.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects; D005910:Glioma / Q000473:pathology*; D006801:Humans; D010087:Oxides / Q000494:pharmacology*; D021381:Protein Transport / Q000187:drug effects; D019098:Telomerase / Q000187:drug effects* / Q000378:metabolism; D016615:Telomere / Q000187:drug effects* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D001152:Arsenicals; D010087:Oxides; D019098:Telomerase; D000077237:Arsenic Trioxide
keywords: As2O3; glioma; growth inhibition; telomerase; telomere