State Key Laboratory of Natural Medicines, Jiangsu Key Laboratory of Carcinogenesis and Intervention, China Pharmaceutical University, Tongjiaxiang, Nanjing, People's Republic of China.
J Cell Physiol. 2015 May;230(5):1054-63. doi: 10.1002/jcp.24833.
Oroxylin A is a flavonoid extracted from the root of Scutellaria baicalensis Georgi. Our previous research demonstrated that oroxylin A have various anti-tumor effects including apoptosis, cell cycle arrest, drug-resistant reversion, and others. This paper explores the mechanism how oroxylin A induce apoptosis by regulating uncoupling protein 2 (UCP2) in human colon cancer cells. We found that the inhibition of UCP2 by UCP2 siRNA significantly increased the sensitivity of cells to drugs, reactive oxygen species (ROS) generation and the opening of mitochondrial permeability transition pore (MPTP) of CaCo-2 cells. We also found that UCP2 inhibition could lead to ROS-mediated MPTP activation. Furthermore, we demonstrated that oroxylin A triggered MPTP-dependent pro-apoptotic protein release from mitochondria to matrix and then induced apoptotic cascade by inhibiting UCP2. Intriguingly, the inhibition of UCP2 by oroxylin A was able to block Bcl-2 translocation to the mitochondria, keeping MPTP at open-state. In conclusion, we have demonstrated that UCP2 plays a key role in mitochondrial apoptotic pathway; UCP2s inhibition by oroxylin A triggers the MPTP opening, and promotes the apoptosis in CaCo-2 cells.
白杨素 A 是从黄芩根中提取的一种黄酮类化合物。我们之前的研究表明，白杨素 A 具有多种抗肿瘤作用，包括凋亡、细胞周期阻滞、耐药逆转等。本文探讨了白杨素 A 通过调节人结肠癌细胞中的解偶联蛋白 2（UCP2）诱导细胞凋亡的机制。我们发现，UCP2 siRNA 抑制 UCP2 可显著增加细胞对药物、活性氧（ROS）生成和 CaCo-2 细胞线粒体通透性转换孔（MPTP）开放的敏感性。我们还发现，UCP2 抑制可导致 ROS 介导的 MPTP 激活。此外，我们证明白杨素 A 通过抑制 UCP2 触发 MPTP 依赖性促凋亡蛋白从线粒体向基质释放，然后诱导凋亡级联反应。有趣的是，白杨素 A 对 UCP2 的抑制作用能够阻止 Bcl-2 向线粒体的易位，使 MPTP 保持开放状态。总之，我们已经证明 UCP2 在线粒体凋亡途径中起着关键作用；白杨素 A 通过抑制 UCP2 触发 MPTP 开放，并促进 CaCo-2 细胞凋亡。
