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

Oncogene. 2009 Jan 15;28(2):231-42. doi: 10.1038/onc.2008.385. Epub 2008 Oct 13.


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 (beta1-integrin), CD44, CD49d (alpha4-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibodies / pharmacology
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Boronic Acids / pharmacology*
  • Bortezomib
  • Cell Adhesion / physiology*
  • Cell Adhesion Molecules / physiology
  • Cell Line, Tumor / metabolism
  • Dexamethasone / pharmacology
  • Down-Regulation
  • Doxorubicin / pharmacology
  • Drug Resistance, Neoplasm / drug effects*
  • Drug Resistance, Neoplasm / physiology
  • Gene Expression Regulation, Neoplastic / drug effects
  • Gene Knockdown Techniques
  • Humans
  • Integrin alpha Chains / biosynthesis
  • Integrin alpha Chains / genetics
  • Integrin alpha Chains / physiology*
  • Integrin alpha4 / biosynthesis
  • Integrin alpha4 / genetics
  • Integrin alpha4 / physiology*
  • Integrin alpha4beta1 / physiology*
  • Multiple Myeloma / drug therapy
  • Multiple Myeloma / metabolism*
  • Neoplasm Proteins / biosynthesis
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / physiology*
  • Pyrazines / pharmacology*
  • Vincristine / pharmacology


  • Antibodies
  • Antineoplastic Agents
  • Boronic Acids
  • CDw49d
  • Cell Adhesion Molecules
  • Integrin alpha Chains
  • Integrin alpha4beta1
  • Neoplasm Proteins
  • Pyrazines
  • Integrin alpha4
  • Vincristine
  • Bortezomib
  • Dexamethasone
  • Doxorubicin