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REIC/Dkk-3 overexpression downregulates P-glycoprotein in multidrug-resistant MCF7/ADR cells and induces apoptosis in breast cancer

Cancer Gene Therapy volume 16, pages 65–72 (2009)Cite this article

Abstract

The overexpression of reduced expression in immortalized cells (REIC)/Dickkopf-3 (Dkk-3), a tumor suppressor gene, induced apoptosis in human prostatic and testicular cancer cells. The aim of this study is to examine the potential of REIC/Dkk-3 as a therapeutic target against breast cancer. First, the in vitro apoptotic effect of Ad-REIC treatment was investigated in breast cancer cell lines and the adenovirus-mediated overexpression of REIC/Dkk-3 was thus found to lead to apoptotic cell death in a c-Jun-NH2-kinase (JNK) phosphorylaion-dependent manner. Moreover, an in vivo apoptotic effect and MCF/Wt tumor growth inhibition were observed in the mouse model after intratumoral Ad-REIC injection. As multidrug resistance (MDR) is a major problem in the chemotherapy of progressive breast cancer, the in vitro effects of Ad-REIC treatment were investigated in terms of the sensitivity of multidrug-resistant MCF7/ADR cells to doxorubicin and of the P-glycoprotein expression. Ad-REIC treatment in MCF7/ADR cells also downregulated P-glycoprotein expresssion through JNK activation, and sensitized its drug resistance against doxorubicin. Therefore, not only apoptosis induction but also the reversal of anticancer drug resistance was achieved using Ad-REIC. We suggest that REIC/Dkk-3 is a novel target for breast cancer treatment and that Ad-REIC might be an attractive agent against drug-resistant cancer in combination with conventional antineoplastic agents.

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Acknowledgements

This study was supported by a grant from the Ministry of Education, Culture, Sports, Science and Technology's FY2006 ‘Creation of Innovation Centers for Advanced Interdisciplinary Research Areas’ Scheme in JAPAN. We thank Prof. Kenneth H. Cowan (Derector, Eppley Institute for Research in Cancer and Allied Diseases, UNMC) for the MCF7/ADR cell donation and Hideo Ueki (Okayama University) for his technical assistance. We also thank Prof. Yoshikazu Sugimoto (Department of Chemotherapy, Kyoritsu University of Pharmacy, Tokyo, JAPAN) who kindly provided the MCF-7/MDR cell line.

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Authors and Affiliations

  1. Department of Cancer and Thoracic Surgery, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan

    K Kawasaki, Y Ogasawara, H Doihara & H Date

  2. Department of Urology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan

    M Watanabe, Y Nasu & H Kumon

  3. Innovation Center Okayama for Nanobio-Targeted Therapy, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan

    M Watanabe, K Ochiai, Y Kashiwakura & H Kumon

  4. Department of Cell Biology, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan

    M Sakaguchi & N-h Huh

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  1. K Kawasaki
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Correspondence to H Doihara.

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Kawasaki, K., Watanabe, M., Sakaguchi, M. et al. REIC/Dkk-3 overexpression downregulates P-glycoprotein in multidrug-resistant MCF7/ADR cells and induces apoptosis in breast cancer. Cancer Gene Ther 16, 65–72 (2009). https://doi.org/10.1038/cgt.2008.58

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