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RPN2 gene confers docetaxel resistance in breast cancer

Nature Medicine volume 14, pages 939–948 (2008)Cite this article

A Corrigendum to this article was published on 01 October 2008

Abstract

Drug resistance acquired by cancer cells has led to treatment failure. To understand the regulatory network underlying docetaxel resistance in breast cancer cells and to identify molecular targets for therapy, we tested small interfering RNAs (siRNAs) against 36 genes whose expression was elevated in human nonresponders to docetaxel for the ability to promote apoptosis of docetaxel-resistant human breast cancer cells (MCF7-ADR cells). The results indicate that the downregulation of the gene encoding ribopholin II (RPN2), which is part of an N-oligosaccharyl transferase complex, most efficiently induces apoptosis of MCF7-ADR cells in the presence of docetaxel. RPN2 silencing induced reduced glycosylation of the P-glycoprotein, as well as decreased membrane localization, thereby sensitizing MCF7-ADR cells to docetaxel. Moreover, in vivo delivery of siRNA specific for RPN2 markedly reduced tumor growth in two types of models for drug resistance. Thus, RPN2 silencing makes cancer cells hypersensitive response to docetaxel, and RPN2 might be a new target for RNA interference–based therapeutics against drug resistance.

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Figure 1: RNAi cell transfection array analysis in cultured breast cancer cells.
Figure 2: Apoptosis of MCF7-ADR cells transduced with RPN2 siRNA.
Figure 3: Induction of RPN2 and MDR1 expression by docetaxel treatment.
Figure 4: Delivery of RPN2 siRNA to docetaxel-resistant breast tumors.
Figure 5: RPN2 siRNA regulates glycosylation of P-glycoprotein (P-gp).

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Acknowledgements

Human mammary carcinoma cell lines, MCF7 cells and multidrug-resistant MCF7-ADR cells were provided by Shien-Lab, Medical Oncology, National Cancer Center Hospital of Japan. We gratefully thank S. Noguchi for the initiation of the whole project and for helpful discussion. We also thank H. Inaji, K. Yoshioka and K. Itoh for their kind assistance; J. Miyazaki (Osaka University) for the kind gift of CAG promoter; and A. Inoue and M. Wada for their excellent technical work. This work was supported in part by a grant-in-aid for the Third-Term Comprehensive 10-Year Strategy for Cancer Control of Japan; a grant-in-aid for Scientific Research on Priority Areas Cancer from the Japanese Ministry of Education, Culture, Sports, Science and Technology; and the Program for Promotion of Fundamental Studies in Health Sciences of the National Institute of Biomedical Innovation of Japan.

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Authors and Affiliations

  1. Section for Studies on Metastasis, Japanese National Cancer Center Research Institute, 1-1, Tsukiji, 5-chome, Chuo-ku, 104-0045, Tokyo, Japan

    Kimi Honma, Fumitaka Takeshita, Yusuke Yamamoto & Takahiro Ochiya

  2. Koken Bioscience Institute, KOKEN, 2-13-10 Ukima, Kita-ku, 115-0051, Tokyo, Japan

    Kimi Honma

  3. Research Institute, Osaka Medical Center for Cancer and Cardiovascular Diseases, 1-3-2 Nakamichi, Higashinari-ku, 537-8511, Osaka, Japan

    Kyoko Iwao-Koizumi & Kikuya Kato

  4. Genetics Division, Japanese National Cancer Center Research Institute, 1-1, Tsukiji, 5-chome, Chuo-ku, 104-0045, Tokyo, Japan

    Teruhiko Yoshida

  5. Pharmaceutical Division, Japanese National Cancer Center Research Institute, 1-1, Tsukiji, 5-chome, Chuo-ku, 104-0045, Tokyo, Japan

    Kazuto Nishio

  6. Dainippon Sumitomo Pharma, 3-45, Kurakakiuchi, 1-chome, Ibaraki, 567-0878, Osaka, Japan

    Shunji Nagahara

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Contributions

K.H. performed the experimental work, data analysis and writing of the first draft of the manuscript. K.K. and T.O. selected the initial set of genes subjected to the screening. K.I.-K., K.K., T.Y. and T.O. participated in the conception, design and coordination of the study. F.T. and Y.Y. performed siRNA delivery in vivo and helped with data analysis. K.N. provided drug-resistant cell lines. S.N. provided delivery molecules. The manuscript was finalized by T.O. with the assistance of all authors.

Corresponding author

Correspondence to Takahiro Ochiya.

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Honma, K., Iwao-Koizumi, K., Takeshita, F. et al. RPN2 gene confers docetaxel resistance in breast cancer. Nat Med 14, 939–948 (2008). https://doi.org/10.1038/nm.1858

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