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Bortezomib overcomes cell adhesion-mediated drug resistance through downregulation of VLA-4 expression in multiple myeloma

Oncogene volume 28, pages 231–242 (2009)Cite this article

Abstract

Multiple myeloma (MM) is incurable, mainly because of cell adhesion-mediated drug resistance (CAM-DR). In this study, we performed functional screening using short hairpin RNA (shRNA) to define the molecule(s) responsible for CAM-DR of MM. Using four bona fide myeloma cell lines (KHM-1B, KMS12-BM, RPMI8226 and U266) and primary myeloma cells, we identified CD29 (β1-integrin), CD44, CD49d (α4-integrin, a subunit of VLA-4), CD54 (intercellular adhesion molecule-1 (ICAM-1)), CD138 (syndecan-1) and CD184 (CXC chemokine receptor-4 (CXCR4)) as major adhesion molecules expressed on MM. shRNA-mediated knockdown of CD49d but not CD44, CD54, CD138 and CD184 significantly reversed CAM-DR of myeloma cells to bortezomib, vincristine, doxorubicin and dexamethasone. Experiments using blocking antibodies yielded almost identical results. Bortezomib was relatively resistant to CAM-DR because of its ability to specifically downregulate CD49d expression. This property was unique to bortezomib and was not observed in other anti-myeloma drugs. Pretreatment with bortezomib was able to ameliorate CAM-DR of myeloma cells to vincristine and dexamethasone. These results suggest that VLA-4 plays a critical role in CAM-DR of MM cells. The combination of bortezomib with conventional anti-myeloma drugs may be effective in overcoming CAM-DR of MM.

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Acknowledgements

This study was supported in part by grants from the Ministry of Health, Welfare, and Labor of Japan, and Grants-in-Aid for Scientific Research from the Ministry of Education, Science, Sports, and Technology of Japan. KN-H and JK are winners of the Jichi Medical School Young Investigator Award.

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  1. K Hatano and J Kikuchi: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology, Department of Internal Medicine, Jichi Medical University, Tochigi, Japan

    K Hatano, M Takatoku, M Ueda, M Nobuyoshi, I Oh, K Sato, T Suzuki, K Ozaki, M Mori, T Nagai, K Muroi, Y Furukawa & K Ozawa

  2. Division of Stem Cell Regulation, Center for Molecular Medicine, Jichi Medical University, Tochigi, Japan

    J Kikuchi, R Shimizu, T Wada & Y Furukawa

  3. Division of Hematology, Department of Medical Oncology, Tochigi Cancer Center, Tochigi, Japan

    Y Kano

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Correspondence to Y Furukawa.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Hatano, K., Kikuchi, J., Takatoku, M. et al. Bortezomib overcomes cell adhesion-mediated drug resistance through downregulation of VLA-4 expression in multiple myeloma. Oncogene 28, 231–242 (2009). https://doi.org/10.1038/onc.2008.385

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