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

Abstract

Arsenic trioxide (As 2O 3) 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 As 2O 3-induced cytotoxicity. As a proof-of-principle, transfection of EGFP-tagged AQP9 to the hepatoma line Hep3B, not expressing AQP9 and As 2O 3 insensitive, led to membrane AQP9 expression and increased As 2O 3-induced cytotoxicity. Similarly, the chronic myeloid leukemia line K562 expressed low levels of AQP9 and was As 2O 3 insensitive. The K562 EGFP-AQP9 transfectant accumulated significantly higher levels of intracellular arsenic than control K562 EGFP when incubated with As 2O 3, resulting in significantly increased As 2O 3-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 As 2O 3-induced cytotoxicity on incubation with As 2O 3, which might explain the synergism between ATRA and As 2O 3. Therefore, AQP9 controlled arsenic transport and might determine As 2O 3 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 As 2O 3 sensitivity. However, APL and AML with maturation expressed comparable AQP9 levels, suggesting that AQP9 expression was related to granulocytic maturation. © 2007 by The American Society of Hematology.