Brander Cancer Research Institute, Department of Pathology, New York Medical College, Valhalla, NY, USA.
Cell Cycle. 2012 Aug 15;11(16):3132-40. doi: 10.4161/cc.21506. Epub 2012 Aug 8.
Mutations of oncogenes and tumor suppressor genes which activate mTOR through several downstream signaling pathways are common to cancer. Activation of mTOR when combined with inhibition of cell cycle progression or DNA replication stress has previously been shown to promote cell senescence. In the present study, we examined the conditions under which human non-small cell lung carcinoma A549 cells can undergo senescence when treated with the DNA alkylating agent mitomycin C (MMC). While exposure of A549 cells to 0.1 or 0.5 µg/ml of MMC led to their arrest in S phase of the cell cycle and subsequent apoptosis, exposure to 0.01 or 0.02 µg/ml for 6 d resulted in induction of cell senescence and near total (0.01 µg/ml) or total (0.02 µg/ml) elimination of their reproductive potential. During exposure to these low concentrations of MMC, the cells demonstrated evidence of DNA replication stress manifested by expression of γH2AX, p21 (WAF1) and a very low level of EdU incorporation into DNA. The data are consistent with the notion that enduring DNA replication stress in cells known to have activated oncogenes leads to their senescence. It is reasonable to expect that tumors having constitutive activation of oncogenes triggering mTOR signaling may be particularly predisposed to undergoing senescence following prolonged treatment with low doses of DNA damaging drugs.
致癌基因和肿瘤抑制基因的突变通过几种下游信号通路激活 mTOR，这在癌症中很常见。先前已经表明，当 mTOR 被激活并与细胞周期进程或 DNA 复制应激的抑制相结合时，会促进细胞衰老。在本研究中，我们研究了人非小细胞肺癌 A549 细胞在接受 DNA 烷化剂丝裂霉素 C (MMC) 处理时发生衰老的条件。虽然 A549 细胞暴露于 0.1 或 0.5 µg/ml 的 MMC 会导致其细胞周期 S 期停滞和随后的细胞凋亡，但暴露于 0.01 或 0.02 µg/ml 6 天会导致细胞衰老的诱导和几乎完全（0.01 µg/ml）或完全（0.02 µg/ml）消除其生殖能力。在暴露于这些低浓度的 MMC 期间，细胞表现出 DNA 复制应激的证据，表现为 γH2AX、p21 (WAF1) 的表达和 EdU 非常低水平地掺入 DNA。这些数据与这样一种观点一致，即已知激活致癌基因的细胞中持续的 DNA 复制应激会导致其衰老。可以合理地预期，具有持续激活致癌基因触发 mTOR 信号的肿瘤在接受低剂量 DNA 损伤药物的长期治疗后，可能特别容易发生衰老。
