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J. Biol. Chem., Vol. 281, Issue 27, 18401-18407, July 7, 2006

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Enhanced Expression of Multidrug resistance-associated Protein 2 and Reduced Expression of Aquaglyceroporin 3 in an Arsenic-resistant Human Cell Line^*

Te-Chang Lee¹, I-Ching Ho, Wen-Jen Lu, and Jin-ding Huang

From the Institute of Biomedical Sciences, Academia Sinica, Taipei 11529 and the Department of Pharmacology, National Cheng Kung University, Tainan 70101, Taiwan

Arsenic-resistant cells (R15), derived from a human lung adenocarcinoma cell line (CL3), were 10-fold more resistant to sodium arsenite (As(III)). Because R15 cells accumulated less arsenic than parental CL3 cells, this arsenic resistance may be due to higher efflux and/or lower uptake of As(III). We therefore compared expression of the multidrug resistance-associated proteins MRP1, MRP2, and MRP3 in these two cell lines. MRP2 expression was 5-fold higher in R15 cells than in CL3 cells, whereas MRP1 and MRP3 expression levels were similar. Furthermore, verapamil and cyclosporin A, inhibitors of multidrug resistance transporters, significantly reduced the efflux of arsenic from R15. Thus, increased arsenic extrusion by MRP2 may contribute to arsenic resistance in R15 cells. We also examined the expression of several aquaglyceroporins (AQPs), which mediate As(III) uptake by cells. Little AQP7 or AQP9 mRNA was detected by reverse transcription-PCR in either cell line, whereas AQP3 mRNA expression was 2-fold lower in R15 cells than in CL3 cells. When AQP3 expression in CL3 cells was knocked down by RNA interference, CL3 cells accumulated less arsenic and became more resistant to As(III). Conversely, overexpression of AQP3 in human embryonic kidney 293T cells increased arsenic accumulation, and the cells were more susceptible to As(III) than 293T cells transfected with vector alone. These results suggest that AQP3 is involved in As(III) accumulation. Taken together, our results suggest that enhanced expression of MRP2 and lower expression of AQP3 are responsible for lower arsenic accumulation in arsenic-resistant R15 cells.

Received for publication, February 9, 2006 , and in revised form, April 12, 2006.

^* This study was supported by Grant AS91IBC3PP from the Academia Sinica, Grants NSC 92-2320-B-010-017, NSC93-2320-B-001-053, and NSC92-3112-B006-016 from the National Science Council, and Grant NHRI-EX95-9522BI from the National Health Research Institutes (to T.-C. L.) and Grant NSC93-3112-B006-005 from the National Science Council of the Republic of China (Taipei, Taiwan) (to J.-d. H.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed. Tel.: 886-2-26523055; Fax: 886-2-27829142; E-mail: bmtcl{at}ibms.sinica.edu.tw.

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