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Resistance to anti-microtubule drug-induced cell death is determined by regulation of BimEL expression.
Oncogene ( IF 6.9 ) Pub Date : 2019-02-15 , DOI: 10.1038/s41388-019-0727-4 Weimei Ruan 1 , Gireedhar Venkatachalam 1 , Radoslaw Mikolaj Sobota 1 , Liyan Chen 1 , Loo Chien Wang 1 , Alena Jacobson 1 , Kathirvel Paramasivam 1 , Uttam Surana 1, 2, 3
Oncogene ( IF 6.9 ) Pub Date : 2019-02-15 , DOI: 10.1038/s41388-019-0727-4 Weimei Ruan 1 , Gireedhar Venkatachalam 1 , Radoslaw Mikolaj Sobota 1 , Liyan Chen 1 , Loo Chien Wang 1 , Alena Jacobson 1 , Kathirvel Paramasivam 1 , Uttam Surana 1, 2, 3
Affiliation
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Anti-microtubule agents are frequently used as anticancer therapeutics. Cell death induced by these agents is considered to be due to sustained mitotic arrest caused by the activation of spindle assembly checkpoint (SAC). However, some cell types are resistant to mitotic cell death. Cells' ability to escape mitotic arrest (mitotic slippage) is thought to be a major mechanism contributing to this resistance. Here, we show that resistance to cell death induced by anti-mitotic agents is not linked to cells' capacity to undergo mitotic slippage as generally believed but is dependent on the state of BimEL regulation during mitosis. While transcriptional repression of BimEL in the mitotic death-resistant cells involves polycomb repressive complex 2 (PRC2)-mediated histone trimethylation, the BimEL protein is destabilized by cullin 1/4A-βTrCP-dependent degradation involving activation of cullin 1/4A by neddylation. These results imply that pharmacological augmentation of BimEL activity in anti-microtubule drug-resistant tumors may have important therapeutic implications.
中文翻译：
对抗微管药物诱导的细胞死亡的抗性由BimEL表达的调节来确定。
抗微管剂经常被用作抗癌治疗剂。这些药物诱导的细胞死亡被认为是由于纺锤体装配检查点（SAC）激活引起的持续有丝分裂停滞。但是，某些细胞类型对有丝分裂细胞死亡具有抗性。细胞逃脱有丝分裂阻滞（有丝分裂滑移）的能力被认为是导致这种抗性的主要机制。在这里，我们显示出对抗有丝分裂剂诱导的细胞死亡的抗性并不像通常认为的那样与细胞经历有丝分裂滑移的能力有关，而是取决于有丝分裂过程中BimEL调控的状态。虽然在有丝分裂死亡抗性细胞中BimEL的转录抑制涉及多梳抑制复合物2（PRC2）介导的组蛋白三甲基化，BimEL蛋白因cullin 1 /4A-βTrCP依赖性降解而不稳定，该降解涉及通过neddylation激活cullin 1 / 4A。这些结果表明，在抗微管耐药性肿瘤中，BimEL活性的药理学增强可能具有重要的治疗意义。
更新日期：2019-02-15
中文翻译：
对抗微管药物诱导的细胞死亡的抗性由BimEL表达的调节来确定。
抗微管剂经常被用作抗癌治疗剂。这些药物诱导的细胞死亡被认为是由于纺锤体装配检查点（SAC）激活引起的持续有丝分裂停滞。但是，某些细胞类型对有丝分裂细胞死亡具有抗性。细胞逃脱有丝分裂阻滞（有丝分裂滑移）的能力被认为是导致这种抗性的主要机制。在这里，我们显示出对抗有丝分裂剂诱导的细胞死亡的抗性并不像通常认为的那样与细胞经历有丝分裂滑移的能力有关，而是取决于有丝分裂过程中BimEL调控的状态。虽然在有丝分裂死亡抗性细胞中BimEL的转录抑制涉及多梳抑制复合物2（PRC2）介导的组蛋白三甲基化，BimEL蛋白因cullin 1 /4A-βTrCP依赖性降解而不稳定，该降解涉及通过neddylation激活cullin 1 / 4A。这些结果表明，在抗微管耐药性肿瘤中，BimEL活性的药理学增强可能具有重要的治疗意义。
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