title: Relationship of expression of aquaglyceroporin 9 with arsenic uptake and sensitivity in leukemia cells.
abstract: Arsenic trioxide (As2O3) is highly efficacious in acute promyelocytic leukemia (APL). Aquaglyceroporin 9 (AQP9) is a transmembrane protein that may be involved in arsenic uptake. In 10 of 11 myeloid and lymphoid leukemia lines, quantitative polymerase chain reaction (Q-PCR) and Western blotting showed that AQP9 expression correlated positively with As2O3-induced cytotoxicity. As a proof-of-principle, transfection of EGFP-tagged AQP9 to the hepatoma line Hep3B, not expressing AQP9 and As2O3 insensitive, led to membrane AQP9 expression and increased As2O3-induced cytotoxicity. Similarly, the chronic myeloid leukemia line K562 expressed low levels of AQP9 and was As2O3 insensitive. The K562(EGFP-AQP9) transfectant accumulated significantly higher levels of intracellular arsenic than control K562(EGFP) when incubated with As2O3, resulting in significantly increased As2O3-induced cytotoxicity. Pretreatment of the myeloid leukemia line HL-60 with all-trans retinoic acid (ATRA) up-regulated AQP9, leading to a significantly increased arsenic uptake and As2O3-induced cytotoxicity on incubation with As2O3, which might explain the synergism between ATRA and As2O3. Therefore, AQP9 controlled arsenic transport and might determine As2O3 sensitivity. Q-PCR showed that primary APL cells expressed AQP9 significantly (2-3 logs) higher than other acute myeloid leukemias (AMLs), which might explain their exquisite As2O3 sensitivity. However, APL and AML with maturation expressed comparable AQP9 levels, suggesting that AQP9 expression was related to granulocytic maturation.
authors.affiliation: Department of Medicine, University of Hong Kong, Professorial Block, Queen Mary Hospital, Pokfulam Road, Hong Kong, China.
authors.forename: Jordy
authors.initials: J
authors.lastname: Leung
authors.forename: Annie
authors.initials: A
authors.lastname: Pang
authors.forename: Wai-Hung
authors.initials: WH
authors.lastname: Yuen
authors.forename: Yok-Lam
authors.initials: YL
authors.lastname: Kwong
authors.forename: Eric W C
authors.initials: EW
authors.lastname: Tse
mesh_terms: D000208:Acute Disease; D020346:Aquaporins / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D020869:Gene Expression Profiling; D006801:Humans; D020014:K562 Cells; D007951:Leukemia, Myeloid / Q000378:metabolism*; D015473:Leukemia, Promyelocytic, Acute / Q000188:drug therapy* / Q000378:metabolism*; D010087:Oxides / Q000378:metabolism / Q000493:pharmacokinetics / Q000494:pharmacology*; D017354:Point Mutation; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012680:Sensitivity and Specificity; D014212:Tretinoin / Q000494:pharmacology; D015854:Up-Regulation / Q000187:drug effects
chemical_list: C109669:AQP9 protein, human; D020346:Aquaporins; D001152:Arsenicals; D010087:Oxides; D014212:Tretinoin; D000077237:Arsenic Trioxide