Bortezomib blocks Bax degradation in malignant B cells during treatment with TRAIL.
Proapoptotic Bcl-2 family member Bax is a crucial protein in the induction of apoptosis, and its activation is required for this process. Here we report that Bax is a short-lived protein in malignant B cells and Bax protein levels decreased rapidly when protein synthesis was blocked. Malignant B cells were relatively resistant to tumor necrosis factor-related apoptosis inducing ligand (TRAIL)-induced apoptosis, and this correlated with low basal Bax protein levels. Furthermore, during treatment with TRAIL, the resistant cell lines showed prominent Bax degradation activity. This degradation activity was localized to mitochondrial Bax and could be prevented by truncated Bid, a BH3-only protein; in contrast, cytosolic Bax was relatively stable. The proteasome inhibitor bortezomib is a potent drug in inducing apoptosis in vitro in malignant B-cell lines and primary chronic lymphocytic leukemic (CLL) cells. In CLL cells, bortezomib induced Bax accumulation, translocation to mitochondria, conformational change, and oligomerization. Accumulation and stabilization of Bax protein by bortezomib-sensitized malignant B cells to TRAIL-induced apoptosis. This study reveals that Bax instability confers resistance to TRAIL, which can be reversed by Bax stabilization with a proteasome inhibitor.
Liu
Feng-Ting
FT
Centre for Haematology, Institute of Cell and Molecular Sciences, Barts and the London, Queen Mary University of London, 4 Newark Street, London, UK.
Agrawal
Samir G
SG
Gribben
John G
JG
Ye
Hongtao
H
Du
Ming-Qing
MQ
Newland
Adrian C
AC
Jia
Li
L
D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D051023:BH3 Interacting Domain Death Agonist Protein / Q000378:metabolism; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D025821:Polyubiquitin / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000187:drug effects*; D011719:Pyrazines / Q000494:pharmacology*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000494:pharmacology*; D013816:Thermodynamics; D014407:Tumor Cells, Cultured; D054875:Ubiquitination / Q000187:drug effects; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism*
D000970:Antineoplastic Agents; D051023:BH3 Interacting Domain Death Agonist Protein; D001897:Boronic Acids; D011719:Pyrazines; D053221:TNF-Related Apoptosis-Inducing Ligand; D051028:bcl-2-Associated X Protein; D025821:Polyubiquitin; D000069286:Bortezomib