title: Inhibition of tankyrase 1 in human gastric cancer cells enhances telomere shortening by telomerase inhibitors.
abstract: Telomere stability is believed to be related to aging and tumorigenesis. Besides telomerase, telomere length is also regulated by several telomere-specific binding proteins. Tankyrase 1, a telomeric poly(ADP-ribose) polymerase (PARP), elongates telomere length by inhibiting TRF1 binding to telomeres. In order to study the synergistic action of tankyrase 1 and telomerase in the maintenance of telomere length in mammalian cells, we constructed anti-sense tankyrase 1 (aTNKS) eukaryotic expression vectors and then transfected them into the SGC-7901 human gastric cancer cell line, as well as SGC-7901 cells that had been transfected with antisense hTR (7901-ahTR) and antisense hTERT (7901-ahTERT) with DOTAP liposomes. The activity of telomerase, telomere length and telomerase-associated protein activities were measure by TRAP-ELISA, Southern blot and western blot analysis, respectively, in aTNKS transfected and untransfected cells. The results demonstrated that telomere length was significantly shorter in cells with concomitant tankyrase 1 and telomerase inhibition than by either tankyrase 1 or telomerase inhibition alone, in SGC-7901 cells. We also found that aTNKS had no effect on telomerase activity. These results reveal that inhibition of tankyrase 1 could shorten telomere length and play a synergistic role with telomerase inhibitors in telomere length shortening in the SGC-7901 gastric cancer cell line. Co-inhibition of tankyrase 1 and telomerase activity may be a rational strategy for telomere-directed gastric cancer therapeutics.
authors.affiliation: Institute of Gastroenterology, Southwest Hospital, Third Military Medical University, Chongqing 400038, P.R. China.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Meng-Hua
authors.initials: MH
authors.lastname: Yang
authors.forename: Jing-Jing
authors.initials: JJ
authors.lastname: Zhao
authors.forename: Ling
authors.initials: L
authors.lastname: Chen
authors.forename: Song-Tao
authors.initials: ST
authors.lastname: Yu
authors.forename: Xu-Dong
authors.initials: XD
authors.lastname: Tang
authors.forename: Dian-Chun
authors.initials: DC
authors.lastname: Fang
authors.forename: Shi-Ming
authors.initials: SM
authors.lastname: Yang
mesh_terms: D015139:Blotting, Southern; D015153:Blotting, Western; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013274:Stomach Neoplasms / Q000201:enzymology* / Q000235:genetics*; D038501:Tankyrases / Q000378:metabolism*; D019098:Telomerase / Q000378:metabolism*; D016615:Telomere / Q000187:drug effects / Q000378:metabolism*; D014162:Transfection
chemical_list: D004791:Enzyme Inhibitors; D038501:Tankyrases; D019098:Telomerase; C418109:TNKS protein, human