title: Anion exchanger 2 mediates the action of arsenic trioxide.
abstract: Anion exchanger 2 (AE2) mediates the exchange of C1-/HCO3- across the plasma membrane and plays a role in the regulation of intracellular pH. The present study showed that AE2 protein expression was upregulated immediately after exposure to either low (0.5 micromol/l) or high (1 and 2 micromol/l) concentrations of arsenic trioxide. This suggests that arsenic trioxide may act via regulation of intracellular pH. Changing the culture pH in NB4 cells modulated the degradation of promyelocytic leukaemia-retinoic acid receptor-alpha (PML-RARalpha), PML and RARalpha, which supported this hypothesis. DIDS (4,4'-diisothiocyanodihydrostilbene-2,2'-disulphonic acid) inhibited AE2 function, preventing the arsenic trioxide-induced degradation of RARalpha and low concentration showed synergistic effects on the expression of CD11c, which is related with cell differentiation. In addition, DIDS rescued the cells from 1 micromol/l arsenic trioxide-induced apoptosis. In conclusion, AE2 mediated the action of arsenic trioxide via regulation of intracellular pH and a novel pathway for the mechanism of action of arsenic trioxide is reported.
authors.affiliation: Department of Pathophysiology, Shanghai Jiao Tong University, School of Medicine.
authors.forename: Xiao-Yan
authors.initials: XY
authors.lastname: Pan
authors.forename: Guo-Qiang
authors.initials: GQ
authors.lastname: Chen
authors.forename: Li
authors.initials: L
authors.lastname: Cai
authors.forename: Stephen
authors.initials: S
authors.lastname: Buscemi
authors.forename: Guo-Hui
authors.initials: GH
authors.lastname: Fu
mesh_terms: D027321:Anion Transport Proteins / Q000494:pharmacology*; D017304:Annexin A5 / Q000032:analysis; D017920:Antiporters / Q000494:pharmacology*; D017209:Apoptosis; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology / Q000627:therapeutic use*; D015415:Biomarkers / Q000032:analysis; D015153:Blotting, Western / Q000379:methods; D039481:CD11b Antigen / Q000032:analysis; D039521:CD11c Antigen / Q000032:analysis; D045744:Cell Line, Tumor; D002470:Cell Survival; D005434:Flow Cytometry; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy*; D010087:Oxides / Q000494:pharmacology / Q000627:therapeutic use*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D064606:SLC4A Proteins
chemical_list: D027321:Anion Transport Proteins; D017304:Annexin A5; D017920:Antiporters; D001152:Arsenicals; D015415:Biomarkers; D039481:CD11b Antigen; D039521:CD11c Antigen; D010087:Oxides; D064606:SLC4A Proteins; D000077237:Arsenic Trioxide