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Copper-Transporting P-Type ATPase, ATP7A, Confers Multidrug Resistance and Its Expression Is Related to Resistance to SN-38 in Clinical Colon Cancer

Departments of ¹ Molecular Oncology, ² Internal Medicine, ³ Surgical Oncology and Digestive Surgery, and ⁴ Environmental Medicine, Graduate School of Medical and Dental Sciences, Kagoshima University, Sakuragaoka, Kagoshima, Japan; ⁵ Centre of Cellular and Molecular Biology, School of Biological and Chemical Sciences, Deakin University, Burwood, Victoria, Australia; and ⁶ Graduate School of Pharmaceutical Science, Osaka University, Suita, Osaka, Japan

Requests for reprints: Tatsuhiko Furukawa, Department of Molecular Oncology, Graduate School of Medical and Dental Sciences, Kagoshima University, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan. Phone: 81-99-275-5490; Fax: 81-99-265-9687; E-mail: furukawa{at}m3.kufm.kagoshima-u.ac.jp.

We and others have shown that the copper transporters ATP7A and ATP7B play a role in cellular resistance to cis-diaminedichloroplatinum (II) (CDDP). In this study, we found that ATP7A transfection of Chinese hamster ovary cells (CHO-K1) and fibroblasts isolated from Menkes disease patients enhanced resistance not only to CDDP but also to various anticancer drugs, such as vincristine, paclitaxel, 7-ethyl-10-hydroxy-camptothecin (SN-38), etoposide, doxorubicin, mitoxantron, and 7-ethyl-10-[4-(1-piperidino)-1-piperidino] carbonyloxycamptothecin (CPT-11). ATP7A preferentially localized doxorubicin fluorescence to the Golgi apparatus in contrast to the more intense nuclear staining of doxorubicin in the parental cells. Brefeldin A partially and monensin completely altered the distribution of doxorubicin to the nuclei in the ATP7A-expressing cells. ATP7A expression also enhanced the efflux rates of doxorubicin and SN-38 from cells and increased the uptake of SN-38 in membrane vesicles. These findings strongly suggested that ATP7A confers multidrug resistance to the cells by compartmentalizing drugs in the Golgi apparatus and by enhancing efflux of these drugs, and the trans-Golgi network has an important role of ATP7A-related drug resistance. ATP7A was expressed in 8 of 34 (23.5%) clinical colon cancer specimens but not in the adjacent normal epithelium. Using the histoculture drug response assay that is useful for the prediction of drug sensitivity of clinical cancers, ATP7A-expressing colon cancer cells were significantly more resistant to SN-38 than ATP7A-negative cells. Thus, ATP7A confers resistance to various anticancer agents on cancer cells and might be a good index of drug resistance in clinical colon cancers. [Cancer Res 2007;67(10):4860–7]

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				ATP7A and Drug Resistance and Clinical Drug Resistance Cancer Res., July 1, 2007; 67(13): 6528 - 6528. [Full Text] [PDF]