Deng Jing, Carlson Nicole, Takeyama Kunihiko, Dal Cin Paola, Shipp Margaret, Letai Anthony
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
Cancer Cell. 2007 Aug;12(2):171-85. doi: 10.1016/j.ccr.2007.07.001.
Cancer cells exhibit many abnormal phenotypes that induce apoptotic signaling via the intrinsic, or mitochondrial, pathway. That cancer cells nonetheless survive implies that they select for blocks in apoptosis. Identifying cancer-specific apoptotic blocks is necessary to rationally target them. Using a panel of 18 lymphoma cell lines, we show that a strategy we have developed, BH3 profiling, can identify apoptotic defects in cancer cells and separate them into three main classes based on position in the apoptotic pathway. BH3 profiling identifies cells that require BCL-2 for survival and predicts sensitivity to the BCL-2 antagonist ABT-737. BCL-2 dependence correlates with high levels of proapoptotic BIM sequestered by BCL-2. Strikingly, BH3 profiling can also predict sensitivity to conventional chemotherapeutic agents like etoposide, vincristine, and adriamycin.
癌细胞表现出许多异常表型，这些表型通过内在（即线粒体）途径诱导凋亡信号。然而，癌细胞仍能存活，这意味着它们选择了凋亡阻滞。识别癌症特异性凋亡阻滞对于合理靶向它们是必要的。使用一组18种淋巴瘤细胞系，我们表明我们开发的一种策略——BH3分析，能够识别癌细胞中的凋亡缺陷，并根据其在凋亡途径中的位置将它们分为三大类。BH3分析可识别生存需要BCL-2的细胞，并预测对BCL-2拮抗剂ABT-737的敏感性。BCL-2依赖性与被BCL-2隔离的高水平促凋亡蛋白BIM相关。引人注目的是，BH3分析还可以预测对依托泊苷、长春新碱和阿霉素等传统化疗药物的敏感性。
