Checkpoint kinase 2 is dispensable for regulation of the p53 response but is required for G2/M arrest and cell survival in cells with p53 defects under heat stress
Checkpoint kinase 2 is dispensable for regulation of the p53 response but is required for G2/M arrest and cell survival in cells with p53 defects under heat stress
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DOI：
10.1007/s10495-017-1402-2
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发表时间：
2017-10-01
期刊：
影响因子：
7.2
通讯作者：
Kondo, Takashi
中科院分区：
文献类型：
--
作者：
Furusawa, Yukihiro;Yamanouchi, Yuka;Kondo, Takashi
已知热应激（HS）诱导的热疗可抑制肿瘤细胞增殖并诱导细胞死亡。我们之前证明了检查点激酶1 （Chk1）有助于G(2)/M阻滞和HS下的细胞存活；然而，Chk1的功能类似物Chk2在HS下调控细胞周期和细胞死亡中的作用尚不清楚。在这里，我们使用带有p53靶向shRNA的Molt-4细胞（Molt-4/shp53）和亲代对照细胞（Molt-4/V）来研究Chk2的作用。Chk2抑制抑制HS下Molt-4/V细胞中p53 c端乙酰化，延迟p53靶基因的诱导；然而，Chk2抑制未能抑制HS诱导的细胞凋亡，这表明Chk2在HS下p53依赖性细胞凋亡中是不可缺少的。相反，Chk2抑制可消除G(2)/M阻滞，促进HS诱导的HeLa细胞和Molt-4/shp53细胞死亡。因此，我们首次证明了Chk2是细胞周期阻滞和细胞存活所必需的，特别是在HS下p53缺陷的细胞中。这些发现表明Chk2可能是高温治疗p53突变或缺陷癌症的选择性靶点。
Hyperthermia induced by heat stress (HS) is known to inhibit proliferation and induce cell death in cancer. We previously demonstrated that checkpoint kinase 1 (Chk1) contributes to G(2)/M arrest and cell survival under HS; however, the role of Chk2, a functional analog of Chk1, in regulation of the cell cycle and cell death under HS is still unknown. Here, we addressed the role of Chk2 using Molt-4 cells with p53-targeted shRNA (Molt-4/shp53) and parental control cells (Molt-4/V). Chk2 inhibition suppressed C-terminal acetylation of p53 and delayed the induction of p53-target genes in Molt-4/V cells under HS; however, Chk2 inhibition failed to inhibit apoptosis induced by HS, indicating that Chk2 was dispensable for p53-dependent apoptosis under HS. In contrast, Chk2 inhibition abrogated G(2)/M arrest and promoted cell death induced by HS in HeLa cells and Molt-4/shp53 cells. Thus, we demonstrated for the first time that Chk2 was required for cell cycle arrest and cell survival, particularly in cells with p53 defects under HS. These findings indicated that Chk2 may be a selective target for p53-mutated or -deficient cancer treated with hyperthermia.