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- Title
Bortezomib overcomes cell adhesion-mediated drug resistance through downregulation of VLA-4 expression in multiple myeloma.
- Authors
Hatano, K; Kikuchi, J; Takatoku, M; Shimizu, R; Wada, T; Ueda, M; Nobuyoshi, M; Oh, I; Sato, K; Suzuki, T; Ozaki, K; Mori, M; Nagai, T; Muroi, K; Kano, Y; Furukawa, Y; Ozawa, K
- 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.Oncogene (2009) 28, 231–242; doi:10.1038/onc.2008.385; published online 13 October 2008
- Subjects
MULTIPLE myeloma; CELL adhesion; DRUG resistance; INTEGRINS; CELL lines; VINCRISTINE
- Publication
Oncogene, 2009, Vol 28, Issue 2, p231
- ISSN
0950-9232
- Publication type
Article
- DOI
10.1038/onc.2008.385