The BH3 mimetic ABT-737 induces cancer cell senescence.
The BH3 mimetic ABT-737 induces cancer cell senescence.
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DOI：
10.1158/0008-5472.can-10-1977
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发表时间：
2011-01-15
期刊：
影响因子：
11.2
通讯作者：
Kraft AS
中科院分区：
文献类型：
--
作者：
Song JH;Kandasamy K;Zemskova M;Lin YW;Kraft AS
ABT-737是一种小分子细胞渗透性Bcl-2拮抗剂，通过模拟BH 3蛋白发挥作用，在多种癌症类型中诱导凋亡性细胞死亡。然而，当与该试剂孵育时，许多实体瘤细胞系不经历凋亡。目前的研究揭示了一种新的机制，即ABT-737在加入耐药癌细胞时具有深远的生物学效应。在PV-10细胞（一种在ABT-737治疗后不死亡的肾细胞癌）中，该药物诱导近430个基因转录的两倍变化。许多这些诱导的mRNA变化是在分泌的蛋白质，IL-6，IL-8和IL-11和趋化因子CXCL 2和CXCL 5，或与“炎性”表型相关的基因。引人注目的是，这些基因变化与先前在细胞衰老中发现的变化高度相似。抗凋亡肾癌、肺癌和前列腺癌细胞系短暂暴露于ABT-737，虽然不能诱导细胞死亡，但会诱导衰老相关β-半乳糖苷酶和细胞生长抑制，与诱导细胞衰老一致。有证据表明，衰老的诱导是由于活性氧升高，随后是半胱天冬酶级联的低水平激活，不足以诱导细胞凋亡，但足以导致轻微的DNA损伤和p53、p21、IL-6和8蛋白的增加。通过显性负性p53蛋白的过度表达，我们发现ABT-737诱导的细胞衰老是p53依赖性的。因此，在ABT-737不能引起细胞死亡的多种癌症类型中，ABT-737可能具有额外的细胞活性，这使得其作为抗癌剂的用途非常有吸引力。
ABT-737, a small molecule cell-permeable Bcl-2 antagonist that acts by mimicking BH3 proteins, induces apoptotic cell death in multiple cancer types. However, when incubated with this agent many solid tumor cell lines do not undergo apoptosis. The current study reveals a novel mechanism whereby ABT-737 when added to apoptosis-resistant cancer cells has profound biologic effects. In PV-10 cells, a renal cell carcinoma that does not die after ABT-737 treatment, this agent induces a two-fold change in the transcription of nearly 430 genes. Many of these induced mRNA changes are in secreted proteins, IL-6, IL-8, and IL-11 and chemokines CXCL2 and CXCL5, or genes associated with an "inflammatory" phenotype. Strikingly, these gene changes are highly similar to those changes previously identified in cellular senescence. Brief exposure of apoptosis-resistant renal, lung and prostate cancer cell lines to ABT-737, although not capable of inducing cell death, causes the induction of senescence-associated β-galactosidase and inhibition of cell growth consistent with the induction of cellular senescence. Evidence indicates that the induction of senescence occurs as a result of reactive oxygen species elevation followed by low-level activation of the caspase cascade, insufficient to induce apoptosis, but sufficient to lead to minor DNA damage and increases in p53, p21, IL-6 and 8 proteins. By overexpression of a dominant-negative p53 protein, we show that ABT-737-induced cellular senescence is p53-dependent. Thus, in multiple cancer types in which ABT-737 is incapable of causing cell death, ABT-737 may have additional cellular activities that make its use as an anticancer agent highly attractive.