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Blood, 1 March 2008, Vol. 111, No. 5, pp. 2797-2805.
Prepublished online as a Blood First Edition Paper on December 26, 2007; DOI 10.1182/blood-2007-08-110445.
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NEOPLASIA
Bortezomib blocks Bax degradation in malignant B cells during treatment with TRAIL
Feng-Ting Liu1,
Samir G. Agrawal1,
John G. Gribben2,
Hongtao Ye3,
Ming-Qing Du3,
Adrian C. Newland1, and
Li Jia1
1 Centre for Haematology, Institute of Cell and Molecular Science,
2 Medical Oncology, Institute of Cancer, Barts and the London Queen Mary, University of London, London; and
3 Division of Molecular Histopathology, Department of Pathology, University of Cambridge, Cambridge, United Kingdom
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.
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