Department of Pharmacy, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Biochem Pharmacol. 2024 Sep;227:116456. doi: 10.1016/j.bcp.2024.116456. Epub 2024 Jul 28.
Furanodienone, a biologically active constituent of sesquiterpenes isolated from Rhizome Curcumae, has been reported to induce apoptosis in human colorectal cancer (CRC) cells by promoting the generation of reactive oxygen species (ROS). However, the source of ROS and how it manipulates apoptosis in CRC cells remains to be elucidated. Herein, we assessed the potential role of the well-known sources of intracellular ROS-mitochondrial electron transport chain and the nicotinamide adenine dinucleotide phosphate oxidases (NOXs), on furanodienone-induced cell death. The results indicated that furanodienone substantially increased the levels of mitochondrial ROS, which were subsequently eliminated by the general NOX inhibitor. Specifically, the nuclear factor kappa-B (NF-κB) translocation triggered a significant rise in the expression of NOX4, an isoform of the NOXs family, upon furanodienone treatment. Nevertheless, the specific NOX4 inhibitor GLX351322 attenuated cell apoptosis and mitochondrial ROS production. As a result, ROS burst induced by furanodienone suppressed the expression of peroxiredoxin1 (PRDX1), a redox signaling protein overexpressed in CRC cells, through a nuclear factor-erythroid-2-related factor 2 (Nrf2)-dependent pathway, thus amplifying the mitogen-activated protein kinases (MAPKs)/p53-mediated apoptotic signaling by increasing the p-p38, p-JNK levels, as well as the cleaved caspases -3, -8 and -9. In vivo experiments further confirmed the anti-proliferative impact of PRDX1 following furanodienone treatment. In summary, the study demonstrated that furanodienone-induced apoptosis in CRC cells is initiated by mitochondrial ROS derived from NOX4, which targeted the PRDX1 and activated the downstream MAPKs/p53-mediated caspase-dependent signaling pathway. Our findings may provide novel insights into the development of adjuvant drugs for CRC treatment and therapeutic applications.
呋喃并二烯酮是从姜黄根茎中分离出的倍半萜烯的一种生物活性成分，据报道，它通过促进活性氧（ROS）的产生来诱导人结直肠癌细胞（CRC）凋亡。然而，ROS 的来源以及它如何操纵 CRC 细胞中的凋亡仍有待阐明。在此，我们评估了细胞内 ROS 的知名来源——线粒体电子传递链和烟酰胺腺嘌呤二核苷酸磷酸氧化酶（NOXs）——在呋喃并二烯酮诱导细胞死亡中的潜在作用。结果表明，呋喃并二烯酮显著增加了线粒体 ROS 的水平，随后被通用的 NOX 抑制剂消除。具体而言，核因子 kappa-B（NF-κB）转位触发了呋喃并二烯酮处理后 NOX4 的表达显著增加，NOX4 是 NOX 家族的一种同工酶。然而，特异性的 NOX4 抑制剂 GLX351322 减弱了细胞凋亡和线粒体 ROS 的产生。结果，ROS 爆发诱导的呋喃并二烯酮通过核因子-红细胞 2 相关因子 2（Nrf2）依赖性途径抑制了过氧化物还原酶 1（PRDX1）的表达，PRDX1 是 CRC 细胞中过表达的一种氧化还原信号蛋白，从而通过增加 p-p38、p-JNK 水平以及切割的 caspase-3、-8 和 -9，放大丝裂原激活蛋白激酶（MAPKs）/p53 介导的凋亡信号。体内实验进一步证实了 PRDX1 继呋喃并二烯酮处理后的抗增殖作用。总之，该研究表明，呋喃并二烯酮诱导 CRC 细胞凋亡是由来自 NOX4 的线粒体 ROS 引发的，NOX4 靶向 PRDX1 并激活下游 MAPKs/p53 介导的 caspase 依赖性信号通路。我们的发现可能为 CRC 治疗的辅助药物开发和治疗应用提供新的思路。
