Point mutation of the proteasome beta5 subunit gene is an important mechanism of bortezomib resistance in bortezomib-selected variants of Jurkat T cell lymphoblastic lymphoma/leukemia line.
To study the mechanism of acquired resistance to bortezomib, a new antitumor drug that is the first therapeutic proteasome inhibitor, we established a series of bortezomib-resistant T lymphoblastic lymphoma/leukemia cell lines, designated the JurkatBs, from the parental Jurkat line via repeated drug selection. There were no significant differences in the growth curves or colony formation between the JurkatB cells and parental Jurkat cells. The effects of bortezomib on cytotoxicity, cell cycle arrest, and induction of apoptosis were decreased in JurkatB cells compared with parental Jurkat cells. A mutation in the proteasome beta5 subunit (PSMB5) gene (G322A), which encodes an amino acid change from Ala to Thr at polypeptide position 108, was detected by sequencing full-length cDNA clones and direct polymerase chain reaction products of the PSMB5 gene. Bortezomib caused less inhibition of chymotrypsin-like activity in resistant cells. When the G322A mutant PSMB5 was retrovirally introduced into parental Jurkat cells, it conferred bortezomib resistance to these cells, resulting in decreased cytotoxicity, apoptosis, and inhibition of chymotrypsin-like activity. The predicted structure of A108T-mutated PSMB5 shows a conformational change that suggests decreased affinity to bortezomib. In short, the G322A mutation of the PSMB5 gene is a novel mechanism for bortezomib resistance.
Lü
Shuqing
S
Department of Hematology, Changhai Hospital, Second Military Medical University, 174 Changhai Road, Shanghai 200433, China.
Yang
Jianmin
J
Song
Xianmin
X
Gong
Shenglan
S
Zhou
Hong
H
Guo
Lieping
L
Song
Ningxia
N
Bao
Xiaochen
X
Chen
Pingping
P
Wang
Jianmin
J
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D002453:Cell Cycle / Q000187:drug effects / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D005822:Genetic Vectors; D006801:Humans; D019169:Jurkat Cells; D017354:Point Mutation; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000235:genetics*; D061988:Proteasome Inhibitors; D011719:Pyrazines / Q000494:pharmacology*; D012190:Retroviridae / Q000235:genetics; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D001897:Boronic Acids; D011480:Protease Inhibitors; D061988:Proteasome Inhibitors; D011719:Pyrazines; D000069286:Bortezomib; C088874:PSMB5 protein, human; D046988:Proteasome Endopeptidase Complex