Relationship of expression of aquaglyceroporin 9 with arsenic uptake and sensitivity in leukemia cells.
Arsenic trioxide (As(2)O(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(2)O(3)-induced cytotoxicity. As a proof-of-principle, transfection of EGFP-tagged AQP9 to the hepatoma line Hep3B, not expressing AQP9 and As(2)O(3) insensitive, led to membrane AQP9 expression and increased As(2)O(3)-induced cytotoxicity. Similarly, the chronic myeloid leukemia line K562 expressed low levels of AQP9 and was As(2)O(3) insensitive. The K562(EGFP-AQP9) transfectant accumulated significantly higher levels of intracellular arsenic than control K562(EGFP) when incubated with As(2)O(3), resulting in significantly increased As(2)O(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(2)O(3)-induced cytotoxicity on incubation with As(2)O(3), which might explain the synergism between ATRA and As(2)O(3). Therefore, AQP9 controlled arsenic transport and might determine As(2)O(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(2)O(3) sensitivity. However, APL and AML with maturation expressed comparable AQP9 levels, suggesting that AQP9 expression was related to granulocytic maturation.[1]References
- Relationship of expression of aquaglyceroporin 9 with arsenic uptake and sensitivity in leukemia cells. Leung, J., Pang, A., Yuen, W.H., Kwong, Y.L., Tse, E.W. Blood (2007) [Pubmed]
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