Jiangsu Key Laboratory for Molecular and Medical Biotechnology, College of Life Sciences, Nanjing Normal University, Nanjing, 210023, PR China.
Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, Shreveport, LA, 71130-3932, USA; Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, 71130-3932, USA.
Int J Biochem Cell Biol. 2020 Apr;121:105715. doi: 10.1016/j.biocel.2020.105715. Epub 2020 Feb 5.
Cadmium (Cd), a heavy metal pollutant, contributes to neurodegenerative disorders. Recently, we have demonstrated that Cd induction of reactive oxygen species (ROS) causes apoptosis in neuronal cells. Whether X-linked inhibitor of apoptosis protein (XIAP) is involved in Cd-induced ROS-dependent neuronal apoptosis remains unclear. Here, we show that Cd-induced ROS reduced the expression of XIAP, which resulted in up-regulation of murine double minute 2 homolog (MDM2) and down-regulation of p53, leading to apoptosis in PC12 cells and primary neurons. Inhibition of MDM2 with Nutlin-3a reversed Cd-induced reduction of p53 and substantially rescued cells from excess ROS-dependent death. Overexpression of XIAP protected against Cd induction of ROS-dependent neuronal apoptosis. Inhibition of XIAP by Embelin strengthened Cd-induced ROS and apoptosis in the cells. Furthermore, we found that Cd inactivation of XIAP pathway was attributed to Cd induction of mitochondrial ROS, as evidenced by using a mitochondrial superoxide indicator MitoSOX and a mitochondria-targeted antioxidant Mito-TEMPO. Taken together, these results indicate that Cd induces mitochondrial ROS inactivation of XIAP-MDM2-p53 pathway leading to apoptosis in neuronal cells. Our findings suggest that activators of XIAP or modulation of XIAP-MDM2-p53 pathway by antioxidants may be exploited for the prevention of Cd-induced oxidative stress and neurodegenerative diseases.
镉（Cd）是一种重金属污染物，可导致神经退行性疾病。最近，我们已经证明，镉诱导的活性氧（ROS）会导致神经元细胞凋亡。但是，凋亡抑制蛋白（XIAP）是否参与镉诱导的 ROS 依赖性神经元凋亡尚不清楚。在这里，我们发现镉诱导的 ROS 降低了 XIAP 的表达，导致鼠双微体 2 同源物（MDM2）上调和 p53 下调，从而导致 PC12 细胞和原代神经元凋亡。用 Nutlin-3a 抑制 MDM2 可逆转 Cd 诱导的 p53 减少，并大大挽救细胞免受过多 ROS 依赖性死亡。XIAP 的过表达可防止 Cd 诱导的 ROS 依赖性神经元凋亡。Embelin 抑制 XIAP 可增强细胞中 Cd 诱导的 ROS 和凋亡。此外，我们发现 Cd 抑制 XIAP 途径归因于 Cd 诱导的线粒体 ROS，这一点可以通过使用线粒体超氧化物指示剂 MitoSOX 和线粒体靶向抗氧化剂 Mito-TEMPO 来证明。总之，这些结果表明，镉诱导的线粒体 ROS 使 XIAP-MDM2-p53 途径失活，导致神经元细胞凋亡。我们的研究结果表明，XIAP 的激活剂或抗氧化剂对 XIAP-MDM2-p53 途径的调节可能被用于预防 Cd 诱导的氧化应激和神经退行性疾病。
