Relationship of expression of aquaglyceroporin 9 with arsenic uptake and sensitivity in leukemia cells

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, AGP9 controlled arsenic transport and might determine As2O3 sensitivity. Q-PCR showed that primary APL cells expressed AGP9 significantly (2-3 logs) higher than other acute myeloid leukemias (AMLs), which might explain their exquisite As2O3 sensitivity. However, APL and AM L with maturation expressed comparable AQP9 levels, suggesting that AQP9 expression was related to granulocytic maturation. (c) 2007 by The American Society of Hematology