title: Telomerase reverse transcriptase inhibition stimulates cyclooxygenase 2 expression in cancer cells and synergizes with celecoxib to exert anti-cancer effects.
abstract: BACKGROUND
  Telomerase and telomerase reverse transcriptase (hTERT) confer cancer cells sustained proliferation and survival potentials. Targeting telomerase or hTERT is a novel anti-cancer strategy. However, telomerase/hTERT inhibition alone has minimal clinical efficacy. We explored the relationship between hTERT and cyclooxygenase 2 (COX2) and evaluated synergistic anti-cancer effects of targeting both hTERT and COX2.
  
  
  METHODS
  hTERT was depleted in gastric and cervical cancer cells using small interfering RNA (siRNA) and analysed for COX2 expression using quantitative PCR and immunoblotting. Viable cells and apoptotic cells in gastric cancer cells treated with hTERT siRNA or/and the COX2 inhibitor celecoxib were measured using Trypen blue exclusion and flow cytometry. The in vivo anti-cancer effect of hTERT depletion or/and celecoxib was evaluated using mouse xenograft models.
  
  
  RESULTS
  Knocking down hTERT expression in cancer cells led to robust increases in mRNA and protein levels of COX2. The COX2 promoter activity increased substantially in hTERT-depleted cells. hTERT depletion led to the activation of p38 mitogen-activated protein kinase responsible for the stimulation of COX2 gene transcription. hTERT depletion or celecoxib alone did not affect cancer cell survival, whereas their combination synergistically killed them both in vitro and in vivo.
  
  
  CONCLUSIONS
  hTERT induces COX2 expression and simultaneously targeting hTERT and COX2 synergistically kills cancer cells.
authors.affiliation: Division of Haematology, Department of Medicine, Centre for Molecular Medicine, CMM, L8:00, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: T
authors.initials: T
authors.lastname: Liu
authors.forename: X
authors.initials: X
authors.lastname: Liang
authors.forename: B
authors.initials: B
authors.lastname: Li
authors.forename: M
authors.initials: M
authors.lastname: Björkholm
authors.forename: J
authors.initials: J
authors.lastname: Jia
authors.forename: D
authors.initials: D
authors.lastname: Xu
mesh_terms: D000818:Animals; D000068579:Celecoxib; D051546:Cyclooxygenase 2 / Q000096:biosynthesis* / Q000235:genetics; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology*; D004357:Drug Synergism; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D051379:Mice; D011401:Promoter Regions, Genetic; D011720:Pyrazoles / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000008:administration & dosage / Q000235:genetics; D013274:Stomach Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D013449:Sulfonamides / Q000494:pharmacology*; D019098:Telomerase / Q000037:antagonists & inhibitors* / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D016615:Telomere / Q000378:metabolism; D014162:Transfection; D015854:Up-Regulation; D002583:Uterine Cervical Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics / Q000628:therapy*; D023041:Xenograft Model Antitumor Assays; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D011720:Pyrazoles; D034741:RNA, Small Interfering; D013449:Sulfonamides; D051546:Cyclooxygenase 2; D048051:p38 Mitogen-Activated Protein Kinases; C509186:TERT protein, human; D019098:Telomerase; D000068579:Celecoxib