Tumor-cell resistance to death receptor-induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax

被引:458
作者
LeBlanc, H
Lawrence, D
Varfolomeev, E
Totpal, K
Morlan, J
Schow, P
Fong, S
Schwall, R
Sinicropi, D
Ashkenazi, A [1 ]
机构
[1] Genentech Inc, Dept Mol Oncol, San Francisco, CA 94080 USA
[2] Genentech Inc, Dept Analyt Assay Technol, San Francisco, CA 94080 USA
[3] Genentech Inc, Dept Immunol, San Francisco, CA 94080 USA
关键词
D O I
10.1038/nm0302-274
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The importance of Bax for induction of tumor apoptosis through death receptors remains unclear. Here we show that Bax can be essential for death receptor-mediated apoptosis in cancer cells. Bax-deficient human colon carcinoma cells were resistant to death-receptor ligands, whereas Bax-expressing sister clones were sensitive. Bax was dispensable for apical death-receptor signaling events including caspase-8 activation, but crucial for mitochondrial changes and downstream caspase activation. Treatment of colon tumor cells deficient in DNA mismatch repair with the death-receptor ligand apo2 ligand (Apo2L)/tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) selected in vitro or in vivo for refractory subclones with Bax frameshift mutations including deletions at a novel site. Chemotherapeutic agents upregulated expression of the Apo2L/TRAIL receptor DR5 and the Bax homolog Bak in Bax(-/-) cells, and restored Apo2L/TRAIL sensitivity in vitro and in vivo. Thus, Bax mutation in mismatch repair-deficient tumors can cause resistance to death receptor-targeted therapy, but pre-exposure to chemotherapy rescues tumor sensitivity.
引用
收藏
页码:274 / 281
页数:8
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