Department of Medicine, University of Illinois, Chicago, Illinois, United States of America.
PLoS One. 2012;7(2):e31761. doi: 10.1371/journal.pone.0031761. Epub 2012 Feb 29.
Irradiation and DNA-damaging chemotherapeutic agents are commonly used in anticancer treatments. Following DNA damage FOXM1 protein levels are often elevated. In this study, we sought to investigate the potential role of FOXM1 in programmed cell death induced by DNA-damage. Human cancer cells after FOXM1 suppression were subjected to doxorubicin or γ-irradiation treatment. Our findings indicate that FOXM1 downregulation by stable or transient knockdown using RNAi or by treatment with proteasome inhibitors that target FOXM1 strongly sensitized human cancer cells of different origin to DNA-damage-induced apoptosis. We showed that FOXM1 suppresses the activation of pro-apoptotic JNK and positively regulates anti-apoptotic Bcl-2, suggesting that JNK activation and Bcl-2 down-regulation could mediate sensitivity to DNA-damaging agent-induced apoptosis after targeting FOXM1. Since FOXM1 is widely expressed in human cancers, our data further support the fact that it is a valid target for combinatorial anticancer therapy.
辐射和破坏 DNA 的化疗药物通常用于癌症治疗。在 DNA 损伤后，FOXM1 蛋白水平通常会升高。在这项研究中，我们试图研究 FOXM1 在 DNA 损伤诱导的程序性细胞死亡中的潜在作用。FOXM1 被抑制后，用人癌细胞进行阿霉素或γ射线处理。我们的研究结果表明，通过 RNAi 稳定或瞬时敲低或通过靶向 FOXM1 的蛋白酶体抑制剂处理下调 FOXM1 可显著增强不同来源的人癌细胞对 DNA 损伤诱导的细胞凋亡的敏感性。我们表明，FOXM1 抑制促凋亡 JNK 的激活，并正向调节抗凋亡 Bcl-2，表明 JNK 激活和 Bcl-2 下调可能介导 FOXM1 靶向治疗后对 DNA 损伤剂诱导的细胞凋亡的敏感性。由于 FOXM1 在人类癌症中广泛表达，我们的数据进一步支持了它是联合抗癌治疗的有效靶点的事实。
