Department of Medicine, University of Illinois at Chicago, Chicago, Illinois 60612, USA.
Am J Pathol. 2013 Jul;183(1):257-65. doi: 10.1016/j.ajpath.2013.03.012. Epub 2013 May 10.
Tumor cells accumulate high level of reactive oxygen species (ROS) because they are metabolically more active than normal cells. Elevated ROS levels increase tumorigenecity but also render cancer cells more vulnerable to oxidative stress than normal cells. The oncogenic transcription factor Forkhead Box M1 (FOXM1), which is overexpressed in a wide range of human cancers, was reported to protect cancer cells from the adverse effects of oxidative stress by up regulating the expression of scavenger enzymes. We therefore hypothesized that the combination of FOXM1 ablation and ROS inducers could selectively eradicate cancer cells. We show that RNA interference-mediated knockdown of FOXM1 further elevates intracellular ROS levels and increases sensitivity of cancer cells to ROS-mediated cell death after treatment with ROS inducers. We also demonstrate that the combination of ROS inducers with FOXM1/proteasome inhibitors induces robust apoptosis in different human cancer cells. In addition, we show evidence that FOXM1/proteasome inhibitor bortezomib in combination with the ROS inducer β-phenylethyl isothiocyanate efficiently inhibits the growth of breast tumor xenografts in nude mice. We conclude that the combination of ROS inducers and FOXM1 inhibitors could be used as a therapeutic strategy to selectively eliminate cancer cells.
肿瘤细胞积累高水平的活性氧（ROS），因为它们比正常细胞具有更高的代谢活性。ROS 水平的升高增加了肿瘤的发生，但也使癌细胞比正常细胞更容易受到氧化应激的影响。致癌转录因子叉头框 M1（FOXM1）在广泛的人类癌症中过度表达，据报道，它通过上调清除酶的表达来保护癌细胞免受氧化应激的不利影响。因此，我们假设 FOXM1 缺失和 ROS 诱导剂的组合可以选择性地消除癌细胞。我们表明，RNA 干扰介导的 FOXM1 敲低进一步提高了细胞内 ROS 水平，并增加了癌症细胞对 ROS 介导的细胞死亡的敏感性，在用 ROS 诱导剂处理后。我们还证明，ROS 诱导剂与 FOXM1/蛋白酶体抑制剂的组合在不同的人类癌细胞中诱导强烈的细胞凋亡。此外，我们提供了证据表明，FOXM1/蛋白酶体抑制剂硼替佐米与 ROS 诱导剂苯乙基异硫氰酸酯联合使用，可有效地抑制裸鼠乳腺癌异种移植瘤的生长。我们得出结论，ROS 诱导剂和 FOXM1 抑制剂的组合可作为一种治疗策略，选择性地消除癌细胞。
