Induction of survivin expression by taxol (paclitaxel) is an early event, which is independent of taxol-mediated G2/M arrest
Induction of survivin expression by taxol (paclitaxel) is an early event, which is independent of taxol-mediated G2/M arrest
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DOI：
10.1074/jbc.m310947200
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发表时间：
2004-04-09
影响因子：
4.8
通讯作者：
Li, FZ
中科院分区：
文献类型：
--
作者：
Ling, X;Bernacki, RJ;Li, FZ
Survivin是一种新的抗凋亡蛋白，在癌症中高表达，但在大多数正常成人组织中检测不到。据报道，紫杉醇介导的癌细胞有丝分裂阻滞与survivin诱导有关，survivin诱导保留了一条存活途径并导致对紫杉醇的抗性。在这项研究中，我们提供了新的证据，证明紫杉醇诱导survivin是一个早期事件，与紫杉醇介导的G(2)/M阻滞无关。紫杉醇处理的MCF-7细胞在4小时内迅速上调survivin表达（3.5-15倍），没有G(2)/M阻滞。与紫杉醇处理后早期相比，延长紫杉醇处理时间（48 h）导致survivin表达降低，但G(2)/M细胞在后期显著增加。有趣的是，3 nM紫杉醇诱导survivin的效果与300 nM相同，比3000 nM更有效。结果表明，3nm紫杉醇对诱导细胞死亡无效。然而，小干扰RNA抑制紫杉醇介导的生存素诱导显著增加紫杉醇介导的细胞死亡。紫杉醇快速激活磷脂酰肌醇3-激酶/Akt和MAPK通路。抑制这些途径可减少存活素诱导并使细胞对紫杉醇介导的细胞死亡敏感。在survivin pla -2840构建体中-1430上游的顺式作用DNA元件至少部分负责紫杉醇介导的survivin诱导。总之，这些数据首次表明，紫杉醇介导的survivin诱导是一个早期事件，并且独立于紫杉醇介导的G(2)/M阻滞。这似乎是癌细胞逃避紫杉醇诱导的凋亡的新机制。靶向这种生存途径可能会导致癌症治疗的新方法。
Survivin is a novel anti-apoptotic protein that is highly expressed in cancer but is undetectable in most normal adult tissues. It was reported that taxol-mediated mitotic arrest of cancer cells is associated with survivin induction, which preserves a survival pathway and results in resistance to taxol. In this study, we provide new evidence that induction of survivin by taxol is an early event and is independent of taxol-mediated G(2)/M arrest. Taxol treatment of MCF-7 cells rapidly up-regulated survivin expression (3.5-15-fold) within 4 h without G(2)/M arrest. Lengthening the treatment of cells (48 h) with taxol resulted in decreased survivin expression in comparison with early times following taxol treatment, although G(2)/M cells were significantly increased at later times. Interestingly, 3 nM taxol induces survivin as effectively as 300 nM and more effectively than 3000 nM. As a result, 3 nM taxol is ineffective at inducing cell death. However, inhibition of taxol-mediated survivin induction by small interfering RNA significantly increased taxol-mediated cell death. Taxol rapidly activated the phosphatidylinositol 3-kinase/Akt and MAPK pathways. Inhibition of these pathways diminished survivin induction and sensitized cells to taxol-mediated cell death. A cis-acting DNA element upstream of -1430 in the survivin pLuc-2840 construct is at least partially responsible for taxol-mediated survivin induction. Together, these data show, for the first time, that taxol-mediated induction of survivin is an early event and independent of taxol-mediated G(2)/M arrest. This appears to be a new mechanism for cancer cells to evade taxol-induced apoptosis. Targeting this survival pathway may result in novel approaches for cancer therapeutics.