Molecular basis of bortezomib resistance: proteasome subunit beta5 (PSMB5) gene mutation and overexpression of PSMB5 protein.
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.
Oerlemans
Ruud
R
Department of Rheumatology, VUMC Institute for Cancer & Immunology, VU University Medical Center, Amsterdam, The Netherlands.
Franke
Niels E
NE
Assaraf
Yehuda G
YG
Cloos
Jacqueline
J
van Zantwijk
Ina
I
Berkers
Celia R
CR
Scheffer
George L
GL
Debipersad
Kabir
K
Vojtekova
Katharina
K
Lemos
Clara
C
van der Heijden
Joost W
JW
Ylstra
Bauke
B
Peters
Godefridus J
GJ
Kaspers
Gertjan L
GL
Dijkmans
Ben A C
BA
Scheper
Rik J
RJ
Jansen
Gerrit
G
D001665:Binding Sites; D001897:Boronic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D000069286:Bortezomib; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D006801:Humans; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D011719:Pyrazines / Q000494:pharmacology* / Q000627:therapeutic use; D034741:RNA, Small Interfering / Q000494:pharmacology
D001897:Boronic Acids; D011719:Pyrazines; D034741:RNA, Small Interfering; D000069286:Bortezomib; C088874:PSMB5 protein, human; D046988:Proteasome Endopeptidase Complex