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首页> 外文期刊>Neoplasia: an international journal for oncology research >Sorafenib Sensitizes Glioma Cells to the BH3 Mimetic ABT-737 by Targeting MCL1 in a STAT3-Dependent Manner
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Sorafenib Sensitizes Glioma Cells to the BH3 Mimetic ABT-737 by Targeting MCL1 in a STAT3-Dependent Manner

机译：Sorafenib通过以STAT3依赖性方式靶向MCL1，使胶质瘤细胞敏感到BH3模拟ABT-737中

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The oncogenic transcription factor signal transducer and activator of transcription 3 (STAT3) is overactivated in malignant glioma and plays a key role in promoting cell survival, thereby increasing the acquired apoptosis resistance of these tumors. Here we investigated the STAT3/myeloid cell leukemia 1 (MCL1) signaling pathway as a target to overcome the resistance of glioma cells to the Bcl-2-inhibiting synthetic BH3 mimetic ABT-737. Stable lentiviral knockdown of MCL1 sensitized LN229 and U87 glioma cells to apoptotic cell death induced by single-agent treatment with ABT-737 which was associated with an early activation of DEVDase activity, cytochrome c release, and nuclear apoptosis. Similar sensitizing effects were observed when ABT-737 treatment was combined with the multikinase inhibitor sorafenib which effectively suppressed levels of phosphorylated STAT3 and MCL1 in MCL1-proficient LN229 and U87 glioma cells. In analogous fashion, these synergistic effects were observed when we combined ABT-737 with the STAT3 inhibitor WP-1066. Lentiviral knockdown of the activating transcription factor 5 combined with subsequent quantitative polymerase chain reaction analysis revealed that sorafenib-dependent suppression of MCL1 occurred at the transcriptional level but did not depend on activating transcription factor 5 which previously had been proposed to be essential for MCL1-dependent glioma cell survival. In contrast, the constitutively active STAT3 mutant STAT3-C was able to significantly enhance MCL1 levels under sorafenib treatment to retain cell survival. Collectively, these data demonstrate that sorafenib targets MCL1 in a STAT3-dependent manner, thereby sensitizing glioma cells to treatment with ABT-737. They also suggest that targeting STAT3 in combination with inducers of the intrinsic pathway of apoptosis may be a promising novel strategy for the treatment of malignant glioma.
机译：转录因子信号传感器和转录3（STAT3）的活化剂在恶性胶质瘤中过度激活，并在促进细胞存活方面发挥关键作用，从而增加了这些肿瘤的获得的凋亡抗性。在这里，我们研究了STAT3 / myeloid细胞白血病1（MCL1）信号通路作为靶向胶质瘤细胞的抗性，抑制BCL-2抑制合成BH3模拟ABT-737。 MCL1致敏LN229和U87胶质瘤细胞的稳定慢病毒敲低对通过ABT-737的单孕治疗诱导的凋亡细胞死亡，其与早期激活Devds活性，细胞色素C释放和核细胞凋亡相关。当ABT-737处理与多喹啉酶抑制剂Sorafenib合并时，观察到类似的敏化效果，其有效地抑制了MCL1-精通LN229和U87胶质瘤细胞中的磷酸化STAT3和MCL1的水平。以类似方式，当我们将ABT-737与STAT3抑制剂WP-1066组合时，观察到这些协同效应。活化转录因子5的慢病毒敲低与随后的定量聚合酶链反应分析表明，在转录水平上发生MCL1的索拉非尼依赖性抑制，但不依赖于先前已经提出的活化转录因子5对MCL1依赖性至关重要的转录因子5胶质瘤细胞存活。相反，组成型活性的STAT3突变体Stat3-C能够显着增强Sorafenib治疗下的MCL1水平以保持细胞存活。总的来说，这些数据表明索拉非尼以统计依赖性方式靶向MCL1，从而敏感胶质瘤细胞与ABT-737治疗。他们还表明，靶向STAT3与细胞凋亡的内在途径的诱导剂组合可能是治疗恶性胶质瘤的有前途的新策略。

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