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Research Articles: Therapeutics, Targets, and Development

ClC-3 expression enhances etoposide resistance by increasing acidification of the late endocytic compartment

¹ Department of Gastroenterology, Charité University Medicine, Campus Virchow-Klinikum, Berlin, Germany and ² Medical Research Council Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Hospital Campus, London, United Kingdom

Requests for reprints: Alessandro Sardini, Medical Research Council Clinical Sciences Centre, Imperial College Faculty of Medicine, Hammersmith Hospital Campus, Du Cane Road, London W12 0NN, United Kingdom. Phone: 44-20-8383-8270; Fax: 44-20-8383-8337. E-mail: a.sardini{at}csc.mrc.ac.uk

Abstract

Resistance to anticancer drugs and consequent failure of chemotherapy is a complex problem severely limiting therapeutic options in metastatic cancer. Many studies have shown a role for drug efflux pumps of the ATP-binding cassette transporters family in the development of drug resistance. ClC-3, a member of the CLC family of chloride channels and transporters, is expressed in intracellular compartments of neuronal cells and involved in vesicular acidification. It has previously been suggested that acidification of intracellular organelles can promote drug resistance by increasing drug sequestration. Therefore, we hypothesized a role for ClC-3 in drug resistance. Here, we show that ClC-3 is expressed in neuroendocrine tumor cell lines, such as BON, LCC-18, and QGP-1, and localized in intracellular vesicles colabeled with the late endosomal/lysosomal marker LAMP-1. ClC-3 overexpression increased the acidity of intracellular vesicles, as assessed by acridine orange staining, and enhanced resistance to the chemotherapeutic drug etoposide by almost doubling the IC₅₀ in either BON or HEK293 cell lines. Prevention of organellar acidification, by inhibition of the vacuolar H⁺-ATPase, reduced etoposide resistance. No expression of common multidrug resistance transporters, such as P-glycoprotein or multidrug-related protein-1, was detected in either the BON parental cell line or the derivative clone overexpressing ClC-3. The probable mechanism of enhanced etoposide resistance can be attributed to the increase of vesicular acidification as consequence of ClC-3 overexpression. This study therefore provides first evidence for a role of intracellular CLC proteins in the modulation of cancer drug resistance. [Mol Cancer Ther 2007;6(3):979–86]

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.

Note: K.H. Weylandt and M. Nebrig contributed equally to this work.

³ Supplementary material for this article are available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/)

Received 8/ 8/06; revised 11/15/06; accepted 1/11/07.

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