title: AS1411-Induced Growth Inhibition of Glioma Cells by Up-Regulation of p53 and Down-Regulation of Bcl-2 and Akt1 via Nucleolin.
abstract: AS1411 binds nucleolin (NCL) and is the first oligodeoxynucleotide aptamer to reach phase I and II clinical trials for the treatment of several cancers. However, the mechanisms by which AS1411 targets and kills glioma cells and tissues remain unclear. Here we report that AS1411 induces cell apoptosis and cycle arrest, and inhibits cell viability by up-regulation of p53 and down-regulation of Bcl-2 and Akt1 in human glioma cells. NCL was overexpressed in both nucleus and cytoplasm in human glioma U87, U251 and SHG44 cells compared to normal human astrocytes (NHA). AS1411 bound NCL and inhibited the proliferation of glioma cells but not NHA, which was accompanied with up-regulation of p53 and down-regulation of Bcl-2 and Akt1. Moreover, AS1411 treatment resulted in the G2/M cell cycle arrest in glioma cells, which was however abolished by overexpression of NCL. Further, AS1411 induced cell apoptosis, which was prevented by silencing of p53 and overexpression of Bcl-2. In addition, AS1411 inhibited the migration and invasion of glioma cells in an Akt1-dependent manner. Importantly, AS1411 inhibited the growth of glioma xenograft and prolonged the survival time of glioma tumor-bearing mice. These results revealed a promising treatment of glioma by oligodeoxynucleotide aptamer.
authors.affiliation: Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China.|Department of Neurosurgery, Harvard Medical School, Boston, United States of America.
authors.forename: Ye
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China.
authors.forename: Gang
authors.initials: G
authors.lastname: Zhao
authors.affiliation: Department of Endocrine, The First Hospital of Jilin University, Changchun, China.
authors.forename: Siwen
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Neurosurgery, Harvard Medical School, Boston, United States of America.
authors.forename: Fares
authors.initials: F
authors.lastname: Nigim
authors.affiliation: Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China.
authors.forename: Guangtong
authors.initials: G
authors.lastname: Zhou
authors.affiliation: Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China.
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Song
authors.affiliation: Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China.
authors.forename: Yong
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Neurosurgery, The First Hospital of Jilin University, Changchun, China.
authors.forename: Yunqian
authors.initials: Y
authors.lastname: Li
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D052157:Aptamers, Nucleotide / Q000494:pharmacology*; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D059565:G2 Phase Cell Cycle Checkpoints / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D005910:Glioma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality / Q000473:pathology; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D008875:Middle Aged; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D009838:Oligodeoxyribonucleotides / Q000494:pharmacology*; D010750:Phosphoproteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays; D000097796:Nucleolin
chemical_list: D000970:Antineoplastic Agents; D052157:Aptamers, Nucleotide; D016328:NF-kappa B; D009838:Oligodeoxyribonucleotides; D010750:Phosphoproteins; D051057:Proto-Oncogene Proteins c-akt; D019253:Proto-Oncogene Proteins c-bcl-2; D016601:RNA-Binding Proteins; D016159:Tumor Suppressor Protein p53; D000097796:Nucleolin; C513936:AGRO 100; C000595707:BCL2 protein, human; C494918:AKT1 protein, human