title: Lithium enhances the antitumour effect of temozolomide against TP53 wild-type glioblastoma cells via NFAT1/FasL signalling.
abstract: BACKGROUND
  We previously showed that activation of the nuclear factor of activated T cells (NFAT)1/Fas ligand (FasL) pathway induces glioma cell death. Lithium (Li) is an inhibitor of glycogen synthase kinase (GSK)-3 that activates NFAT1/FasL signalling. Temozolomide (TMZ) inhibits GSK-3 and activates Fas in tumour protein (TP)53 wild-type (TP53wt) glioma cells. The present study investigated the combinational effects of TMZ and low-dose Li on TP53wt glioma cells.
  
  
  METHODS
  The combined effect of TMZ and Li was examined in TP53wt U87 and primary glioma cells and a mouse xenograft model.
  
  
  RESULTS
  Combination with 1.2 mM Li potentiated TMZ-induced cell death in TP53wt glioma cells, as determined by neurosphere formation and apoptosis assays. Temozolomide combined with Li treatment inhibited GSK-3 activation, promoted NFAT1 nuclear translocation and upregulated Fas/FasL expression. Targeted knockdown of NFAT1 expression blocked the induction of cell death by TMZ and Li via FasL inhibition. In vivo, combined treatment with TMZ and Li suppressed tumour growth and prolonged the survival of tumour-bearing mice. However, the combination of TMZ and Li did not produce a statistically significant effect in TP53mut glioma cells.
  
  
  CONCLUSIONS
  Temozolomide combined with low-dose Li induces TP53wt glioma cell death via NFAT1/FasL signalling. This represents a potential therapeutic strategy for TP53wt glioma treatment.
authors.affiliation: Department of Neurosurgery, The First Hospital of China Medical University, Nanjing Street 155, Heping District, Shenyang 110001, China.
authors.forename: Sheng
authors.initials: S
authors.lastname: Han
authors.affiliation: Department of Neurosurgery, The First Hospital of China Medical University, Nanjing Street 155, Heping District, Shenyang 110001, China.
authors.forename: Lingxuan
authors.initials: L
authors.lastname: Meng
authors.affiliation: Department of Neurosurgery, The First Hospital of China Medical University, Nanjing Street 155, Heping District, Shenyang 110001, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Department of Neurosurgery, The First Hospital of China Medical University, Nanjing Street 155, Heping District, Shenyang 110001, China.
authors.forename: Wen
authors.initials: W
authors.lastname: Cheng
authors.affiliation: Department of Neurosurgery, The First Hospital of China Medical University, Nanjing Street 155, Heping District, Shenyang 110001, China.
authors.forename: Xinxin
authors.initials: X
authors.lastname: Tie
authors.affiliation: Department of Neurosurgery, The First Hospital of China Medical University, Nanjing Street 155, Heping District, Shenyang 110001, China.
authors.forename: Junzhe
authors.initials: J
authors.lastname: Xia
authors.affiliation: Department of Neurosurgery, The First Hospital of China Medical University, Nanjing Street 155, Heping District, Shenyang 110001, China.
authors.forename: Anhua
authors.initials: A
authors.lastname: Wu
mesh_terms: D000368:Aged; D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001932:Brain Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D053222:Fas Ligand Protein / Q000276:immunology / Q000378:metabolism*; D005260:Female; D055785:Gene Knockdown Techniques; D005909:Glioblastoma / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors; D006801:Humans; D008094:Lithium / Q000008:administration & dosage; D008297:Male; D051379:Mice; D008875:Middle Aged; D050778:NFATC Transcription Factors / Q000235:genetics / Q000378:metabolism*; D009368:Neoplasm Transplantation; D061251:Primary Cell Culture; D021381:Protein Transport / Q000187:drug effects; D015398:Signal Transduction / Q000187:drug effects; D015996:Survival Rate; D000077204:Temozolomide; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D057134:Antibodies, Neutralizing; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D050778:NFATC Transcription Factors; C494006:NFATC2 protein, human; D016159:Tumor Suppressor Protein p53; D003606:Dacarbazine; D008094:Lithium; D038362:Glycogen Synthase Kinase 3; D000077204:Temozolomide