Unit of Cellular Signaling, Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel.
Oncogene. 2010 Nov 18;29(46):6149-59. doi: 10.1038/onc.2010.343. Epub 2010 Aug 23.
DNA damage checkpoints cause cell cycle arrest, allowing DNA repair before resumption of the cell cycle. These checkpoints can be activated through several signaling pathways. Checkpoint activators include p53, checkpoint kinase 1 (CHK1), checkpoint kinase 2 and/or MAPKAP kinase 2 (MK2). Many cancer cells lack p53 activity and, therefore, depend on alternative checkpoint activators to arrest the cell cycle following DNA damage. Inhibition of these pathways is expected to specifically sensitize these p53-deficient cells to DNA damage caused by chemotherapy. Using isogenic p53-proficient and p53-deficient cancer cell lines, we show that inactivation of CHK1, but not MK2, abrogates cell cycle arrest following chemotherapy, specifically in p53-deficient cells. However, we show that CHK1 is required to maintain genome integrity and cell viability, and that p53-proficient cells are no less sensitive than p53-deficient cells to CHK1 inhibition in the presence of DNA damage. Thus, combining CHK1 inhibition with DNA damage does not lead to preferential killing of p53-deficient over p53-proficient cells, and inhibiting CHK1 does not appear to be a promising approach for potentiation of cancer chemotherapy.
DNA 损伤检查点会导致细胞周期停滞，从而在细胞周期恢复之前允许进行 DNA 修复。这些检查点可以通过几种信号通路激活。检查点激活剂包括 p53、检查点激酶 1（CHK1）、检查点激酶 2 和/或丝裂原活化蛋白激酶激活的蛋白激酶 2（MK2）。许多癌细胞缺乏 p53 活性，因此，在 DNA 损伤后，它们依赖于替代的检查点激活剂来阻止细胞周期。预计抑制这些途径将特异性地使这些缺乏 p53 的细胞对化疗引起的 DNA 损伤敏感。使用同基因 p53 功能正常和 p53 缺陷的癌细胞系，我们表明，CHK1 的失活，但不是 MK2 的失活，会消除化疗后细胞周期的停滞，特别是在 p53 缺陷的细胞中。然而，我们表明 CHK1 对于维持基因组完整性和细胞活力是必需的，并且在存在 DNA 损伤的情况下，p53 功能正常的细胞对 CHK1 抑制的敏感性并不低于 p53 缺陷的细胞。因此，将 CHK1 抑制与 DNA 损伤相结合不会导致对 p53 缺陷的细胞比 p53 功能正常的细胞有优先杀伤作用，并且抑制 CHK1 似乎不是增强癌症化疗的有前途的方法。
