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首页> 外文期刊>Cell cycle >Selective induction of necrotic cell death in cancer cells by beta-lapachone through activation of DNA damage response pathway.
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Selective induction of necrotic cell death in cancer cells by beta-lapachone through activation of DNA damage response pathway.

机译：β-拉帕酮通过激活DNA损伤反应途径选择性诱导癌细胞中的坏死细胞死亡。

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Most efforts thus far have been devoted to develop apoptosis inducers for cancer treatment. However, apoptotic pathway deficiencies are a hallmark of cancer cells. We propose that one way to bypass defective apoptotic pathways in cancer cells is to induce necrotic cell death. Here we show that selective induction of necrotic cell death can be achieved by activation of the DNA damage response pathways. While beta-lapachone induces apoptosis through E2F1 checkpoint pathways, necrotic cell death can be selectively induced by beta-lapachone in a variety of cancer cells. We found that beta-lapachone, unlike DNA damaging chemotherapeutic agents, transiently activates PARP1, a main regulator of the DNA damage response pathway, both in vitro and in vivo. This occurs within minutes of exposure to beta-lapachone, resulting in selective necrotic cell death. Inhibition of PAR blocked beta-lapachone-induced necrosis. Furthermore, necrotic cell death induced by beta-lapachone was significantly reduced in PARP1 knockout cell lines. Our data suggest that selective necrotic cell death can be induced through activation of DNA damage response pathways, supporting the idea of selective necrotic cell death as a therapeutic strategy to eliminate cancer cells.
机译：迄今为止，大多数努力致力于开发用于癌症治疗的细胞凋亡诱导剂。然而，凋亡途径缺陷是癌细胞的标志。我们提出一种绕过癌细胞中有缺陷的凋亡途径的方法是诱导坏死细胞死亡。在这里，我们表明可以通过激活DNA损伤反应途径来选择性诱导坏死细胞死亡。尽管β-拉帕酮通过E2F1检查点途径诱导凋亡，但坏死性细胞死亡可被β-拉帕酮在多种癌细胞中选择性诱导。我们发现，β-拉帕酮与DNA破坏性化学治疗剂不同，在体外和体内均会瞬时激活PARP1，这是DNA损伤反应途径的主要调节剂。这发生在暴露于β-拉帕酮的几分钟之内，导致选择性坏死细胞死亡。 PAR的抑制阻断了β-拉帕酮诱导的坏死。此外，在PARP1基因敲除细胞系中，β-拉帕酮诱导的坏死细胞死亡显着减少。我们的数据表明，选择性坏死性细胞死亡可以通过激活DNA损伤反应途径来诱导，支持选择性坏死性细胞死亡作为消除癌细胞的治疗策略的想法。

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