Department of Pharmacology and Chemical Biology and Drug Discovery Institutes, University of Pittsburgh, Pittsburgh, PA, USA.
Cell Cycle. 2009 Oct 1;8(19):3157-64. doi: 10.4161/cc.8.19.9704. Epub 2009 Oct 3.
Hypoxia is a common feature of solid tumors and represents a critical factor in their progression and responsiveness to chemotherapy and radiotherapy. We now report that hypoxic exposure of colon cancer cells decreased the protein levels of the cell cycle-controlling phosphatase Cdc25A. Hypoxia decreased the mitotic population and caused S-phase arrest in these cells. Suppression of Cdc25A was phosphatase family member-specific, as a similar decrease was not observed with closely related Cdc25B or Cdc25C phosphatases. Pharmacological and genetic blockade of Chk1 and Chk2 failed to inhibit the hypoxia-mediated loss of Cdc25A, indicating this process was not regulated by a traditional ATM/ATR checkpoint response. In addition, hypoxia did not affect ectopically expressed Cdc25A levels suggesting independence from an increase in proteasomal degradation. Cdc25A mRNA levels also decreased in human colon cancer cells 24 hr after hypoxia supporting a mechanistic role for decreased Cdc25A expression or mRNA stability. The reduction in Cdc25A mRNA and protein was dependent on the cyclin-dependent kinase inhibitor p21 and miR-21, which were upregulated in HCT116 colon cancer cells during hypoxia. These results reveal previously unknown mechanisms for the transient suppression of Cdc25A, providing a coordinated and fundamental adaptive change that may be exploited by cancer cells conferring proliferative and survival advantages.
缺氧是实体肿瘤的常见特征，是其进展以及对化疗和放疗的反应的关键因素。我们现在报告，结肠癌细胞的缺氧暴露降低了细胞周期调控磷酸酶 Cdc25A 的蛋白水平。缺氧降低了有丝分裂群体，并导致这些细胞的 S 期停滞。Cdc25A 的抑制是磷酸酶家族成员特异性的，因为与密切相关的 Cdc25B 或 Cdc25C 磷酸酶没有观察到类似的减少。Chk1 和 Chk2 的药理学和遗传阻断未能抑制缺氧介导的 Cdc25A 丢失，表明该过程不受传统 ATM/ATR 检查点反应的调节。此外，缺氧不影响异位表达的 Cdc25A 水平，表明其独立于蛋白酶体降解的增加。人结肠癌细胞在缺氧后 24 小时 Cdc25A mRNA 水平也降低，支持 Cdc25A 表达或 mRNA 稳定性降低的机制作用。Cdc25A mRNA 和蛋白的减少依赖于细胞周期蛋白依赖性激酶抑制剂 p21 和 miR-21，它们在 HCT116 结肠癌细胞缺氧期间上调。这些结果揭示了 Cdc25A 短暂抑制的先前未知机制，提供了一种协调和基本的适应性变化，可能被癌细胞利用，赋予增殖和生存优势。
