Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein

Blood. 2008 Sep 15;112(6):2489-99. doi: 10.1182/blood-2007-08-104950. Epub 2008 Jun 18.


The proteasome inhibitor bortezomib is a novel anticancer drug that has shown promise in the treatment of refractory multiple myeloma. However, its clinical efficacy has been hampered by the emergence of drug-resistance phenomena, the molecular basis of which remains elusive. Toward this end, we here developed high levels (45- to 129-fold) of acquired resistance to bortezomib in human myelomonocytic THP1 cells by exposure to stepwise increasing (2.5-200 nM) concentrations of bortezomib. Study of the molecular mechanism of bortezomib resistance in these cells revealed (1) an Ala49Thr mutation residing in a highly conserved bortezomib-binding pocket in the proteasome beta5-subunit (PSMB5) protein, (2) a dramatic overexpression (up to 60-fold) of PSMB5 protein but not of other proteasome subunits including PSMB6, PSMB7, and PSMA7, (3) high levels of cross-resistance to beta5 subunit-targeted cytotoxic peptides 4A6, MG132, MG262, and ALLN, but not to a broad spectrum of chemotherapeutic drugs, (4) no marked changes in chymotrypsin-like proteasome activity, and (5) restoration of bortezomib sensitivity in bortezomib-resistant cells by siRNA-mediated silencing of PSMB5 gene expression. Collectively, these findings establish a novel mechanism of bortezomib resistance associated with the selective overexpression of a mutant PSMB5 protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Boronic Acids / pharmacology*
  • Boronic Acids / therapeutic use
  • Bortezomib
  • Cell Line
  • Dose-Response Relationship, Drug
  • Drug Resistance, Neoplasm / genetics*
  • Humans
  • Mutation*
  • Proteasome Endopeptidase Complex / genetics*
  • Pyrazines / pharmacology*
  • Pyrazines / therapeutic use
  • RNA, Small Interfering / pharmacology


  • Boronic Acids
  • Pyrazines
  • RNA, Small Interfering
  • Bortezomib
  • PSMB5 protein, human
  • Proteasome Endopeptidase Complex