Tumor-cell resistance to death receptor-induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax
Tumor-cell resistance to death receptor-induced apoptosis through mutational inactivation of the proapoptotic Bcl-2 homolog Bax
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DOI：
10.1038/nm0302-274
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发表时间：
2002-03-01
期刊：
影响因子：
82.9
通讯作者：
Ashkenazi, A
中科院分区：
文献类型：
--
作者：
LeBlanc, H;Lawrence, D;Ashkenazi, A
Bax通过死亡受体诱导肿瘤细胞凋亡的重要性尚不清楚。本研究表明，Bax对死亡受体介导的癌细胞凋亡至关重要。缺乏bax的人结肠癌细胞对死亡受体配体具有抗性，而表达bax的姊妹克隆对死亡受体配体敏感。Bax对于包括caspase-8激活在内的顶端死亡受体信号事件是必不可少的，但对于线粒体变化和下游caspase激活至关重要。在体外或体内选择死亡受体配体apo2配体(Apo2L)/肿瘤坏死因子相关凋亡诱导配体（TRAIL）治疗DNA错配修复缺陷的结肠肿瘤细胞，用于具有Bax移徙突变（包括新位点缺失）的难治性亚克隆。化疗药物上调Bax（-/-）细胞中Apo2L/TRAIL受体DR5和Bax同源物Bak的表达，在体外和体内恢复Apo2L/TRAIL敏感性。因此，错配修复缺陷肿瘤中的Bax突变可引起对死亡受体靶向治疗的抗性，但预先暴露于化疗可挽救肿瘤敏感性。
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.