BaxΔ2 promotes apoptosis through caspase-8 activation in microsatellite-unstable colon cancer.
BaxΔ2 promotes apoptosis through caspase-8 activation in microsatellite-unstable colon cancer.
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Baxβ2 通过 caspase-8 激活微卫星不稳定结肠癌促进细胞凋亡。
DOI：
10.1158/1541-7786.mcr-14-0162
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Xiang,Jialing
中科院分区：
文献类型：
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作者：
Zhang,Honghong;Lin,Yuting;Mañas,Adriana;Zhao,Yu;Denning,MitchellF;Ma,Li;Xiang,Jialing
微卫星突变导致的Bax细胞凋亡丢失有助于肿瘤的发展和化疗耐药。最近，一个Bax微卫星突变被发现与一个特定的选择性剪接事件相结合，可以在其他Bax阴性细胞中产生一个独特的Bax亚型（BaxΔ2）。与原型Baxα一样，BaxΔ2是一种有效的促凋亡分子。然而，BaxΔ2的促凋亡机制和治疗意义尚不明确。本文描述了代表结直肠癌不同Bax微卫星状态的等基因亚细胞系的分离和分析。携带baxmicrosatellite G7/G7等位基因的结肠癌细胞能够产生低水平的内源性BaxΔ2转录本和蛋白质。有趣的是，与BaxΔ2-negative细胞相比，BaxΔ2-positive细胞对化疗药物的一个亚组具有选择性敏感性。与其他Bax亚型不同，BaxΔ2将caspase-8招募到附近进行激活，而后者反过来激活caspase-3和细胞凋亡，而不依赖于线粒体途径。这些数据表明BaxΔ2的表达可能为bax阴性肿瘤提供替代的凋亡和化疗优势。意义：表达Bax亚型的“Bax阴性”结直肠肿瘤对选择性化疗敏感。Mol - Cancer Res；12 (9);1225 - 32。AACR©2014。
Loss of apoptotic Bax due to microsatellite mutation contributes to tumor development and chemoresistance. Recently, a Bax microsatellite mutation was uncovered in combination with a specific alternative splicing event that could generate a unique Bax isoform (BaxΔ2) in otherwise Bax-negative cells. Like the prototype Baxα, BaxΔ2 is a potent proapoptotic molecule. However, the proapoptotic mechanism and therapeutic implication of BaxΔ2 remain elusive. Here, the isolation and analysis of isogenic subcell lines are described that represent different Bax microsatellite statuses from colorectal cancer. Colon cancer cells harboringBaxmicrosatellite G7/G7 alleles are capable of producing low levels of endogenous BaxΔ2 transcripts and proteins. Interestingly, BaxΔ2-positive cells are selectively sensitive to a subgroup of chemotherapeutics compared with BaxΔ2-negative cells. Unlike other Bax isoforms, BaxΔ2 recruits caspase-8 into the proximity for activation, and the latter, in turn, activates caspase-3 and apoptosis independent of the mitochondrial pathway. These data suggest that the expression of BaxΔ2 may provide alternative apoptotic and chemotherapeutic advantages for Bax-negative tumors.Implications:“Bax-negative” colorectal tumors expressing a Bax isoform are sensitive to selective chemotherapeutics.Mol Cancer Res; 12(9); 1225–32. ©2014 AACR.