Bortezomib-resistant myeloma cell lines: a role for mutated PSMB5 in preventing the accumulation of unfolded proteins and fatal ER stress

Leukemia. 2010 Aug;24(8):1506-12. doi: 10.1038/leu.2010.137. Epub 2010 Jun 17.


Bortezomib is an effective agent for treating multiple myeloma (MM). To investigate the underlying mechanisms associated with acquired resistance to this agent, we established two bortezomib-resistant MM cell lines, KMS-11/BTZ and OPM-2/BTZ, the 50% inhibitory concentration values of which were respectively 24.7- and 16.6-fold higher than their parental cell lines. No activation of caspase and BH3-only proteins such as Noxa was noted in bortezomib-resistant cells after exposure to the drug. The accumulation of polyubiquitinated proteins was reduced in bortezomib-resistant cells compared with the parental cells, associated with avoidance of catastrophic ER stress as assessed by downregulation of CHOP expression. These resistant MM cells have a unique point mutation, G322A, in the gene encoding the proteasome beta5 subunit (PSMB5), likely resulting in conformational changes to the bortezomib-binding pocket of this subunit. KMS-11 parental cells transfected to express mutated PSMB5 also showed reduced bortezomib-induced apoptosis compared with those expressing wild-type PSMB5 or the parental cells. Expression of mutated PSMB5 was associated with the prevention of the accumulation of unfolded proteins. Thus, a fraction of MM cells may acquire bortezomib resistance by suppressing apoptotic signals through the inhibition of unfolded protein accumulation and subsequent excessive ER stress by a mutation of the PSMB5 gene.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis
  • Base Sequence
  • Boronic Acids / pharmacology*
  • Bortezomib
  • Cell Line, Tumor
  • Cell Proliferation
  • DNA Primers
  • Drug Resistance, Neoplasm / genetics
  • Endoplasmic Reticulum / metabolism*
  • Humans
  • Multiple Myeloma / pathology*
  • Mutation*
  • Neoplasm Proteins / metabolism*
  • Point Mutation
  • Proteasome Endopeptidase Complex / genetics*
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Denaturation
  • Pyrazines / pharmacology*
  • Ubiquitin / metabolism


  • Antineoplastic Agents
  • Boronic Acids
  • DNA Primers
  • Neoplasm Proteins
  • Pyrazines
  • Ubiquitin
  • Bortezomib
  • PSMB5 protein, human
  • Proteasome Endopeptidase Complex