NF-κB and Poly (ADP-ribose) Polymerase 1 Form a Positive Feedback Loop that Regulates DNA Repair in Acute Myeloid Leukemia Cells
NF-κB and Poly (ADP-ribose) Polymerase 1 Form a Positive Feedback Loop that Regulates DNA Repair in Acute Myeloid Leukemia Cells
复制标题
NF-κB 和聚（ADP-核糖）聚合酶 1 形成正反馈环，调节急性髓系白血病细胞中的 DNA 修复。
DOI：
10.1158/1541-7786.mcr-18-0523
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发表时间：
2019-03-01
影响因子：
5.2
通讯作者：
Wu, Lixian
中科院分区：
文献类型：
--
作者：
Li, Ding;Luo, Yufei;Wu, Lixian
NF-kB mediates acquired resistance in acute myeloid leukemia (AML) cells treated with DNA-damaging agents. Because DNA repair is the major molecular shift that alters sensitivity to DNA-damaging agents, we explored whether activation of the NF-kB pathway promotes AML cell survival by regulating DNA repair after chemotherapy. Our results showed that RELA, an important subunit of NF-kB, regulated DNA repair by binding to the promoter region of the PARP1 gene and affecting PARP1 gene transcription. Conversely, PARP1 knockdown reduced NF-kB activity, indicating that NF-kB and PARP1 create a positive feedback loop in DNA repair. Simultaneous treatment with the NF-kB inhibitor BMS-345541 and the PARP1 inhibitor olaparib resulted in robust killing of AML cells. This dual inhibition significantly suppressed tumor growth and extended survival times in xenograft tumor models.Implications: RELA and PARP1 form a positive feedback loop to regulate DNA damage repair, simultaneous inhibition of NF-kB and PARP1 increases the antileukemic efficacy of daunorubicin in vitro and in vivo, broadening the use of PARP1 inhibitors.
