Department of Pediatrics, Herman B Wells Center for Pediatrics Research, Indianapolis, Indiana, United States of America.
PLoS One. 2013 Sep 6;8(9):e74741. doi: 10.1371/journal.pone.0074741. eCollection 2013.
Serdemetan (JNJ-26854165), an antagonist to Mdm2, was anticipated to promote the activation of p53. While regulation of p53 by Mdm2 is important, Mdm2 also regulates numerous proteins involved in diverse cellular functions. We investigated if Serdemetan would alter the Mdm2-HIF1α axis and affect cell survival in human glioblastoma cells independently of p53. Treatment of cells with Serdemetan under hypoxia resulted in a decrease in HIF1α levels. HIF1α downstream targets, VEGF and the glycolytic enzymes (enolase, phosphoglycerate kinase1/2, and glucose transporter 1), were all decreased in response to Serdemetan. The involvement of Mdm2 in regulating gene expression of glycolytic enzymes raises the possibility of side effects associated with therapeutically targeting Mdm2.
色瑞替尼（JNJ-26854165），一种 Mdm2 的拮抗剂，有望促进 p53 的激活。虽然 Mdm2 对 p53 的调节很重要，但 Mdm2 还调节许多参与多种细胞功能的蛋白质。我们研究了色瑞替尼是否会改变 Mdm2-HIF1α 轴，并在不依赖于 p53 的情况下影响人胶质母细胞瘤细胞的存活。在缺氧条件下用色瑞替尼处理细胞会导致 HIF1α 水平降低。HIF1α 的下游靶标，VEGF 和糖酵解酶（烯醇酶、磷酸甘油酸激酶 1/2 和葡萄糖转运蛋白 1），均因色瑞替尼而减少。Mdm2 参与调节糖酵解酶的基因表达，这增加了与靶向 Mdm2 治疗相关的副作用的可能性。
