Department of Respiratory Medicine, The Second Affiliated Hospital of Soochow University, Suzhou, China.
Kaohsiung J Med Sci. 2019 Apr;35(4):202-208. doi: 10.1002/kjm2.12051. Epub 2019 Mar 21.
The proto-oncogene MDM2 is a nuclear-localized E3 ubiquitin ligase, which promotes tumor formation by targeting tumor suppressor proteins, such as p53, for proteasomal degradation. In this study, the anti-infective drug nitroxoline (NXQ) was screened out to effectively inhibit cell survival of small-cell lung cancer (SCLC) cells, and induce SCLC cell apoptosis by suppressing antiapoptotic proteins (such as Bcl-2 and MCL1) and upregulating proapoptotic protein Bim. In the mechanistic study, NXQ was found to downregulate MDM2 expression by inducing its proteasomal degradation, and thus upregulated p53 expression, which was a substrate protein of MDM2. Moreover, overexpression of MDM2 decreased the cytotoxicity of NXQ on SCLC cells. These results demonstrated that NXQ displayed anti-SCLC activity by suppressing MDM2 expression, which suggested that anti-infective NXQ had potential for SCLC treatment by targeting the MDM2/p53 axis.
原癌基因 MDM2 是一种核定位的 E3 泛素连接酶，通过靶向肿瘤抑制蛋白（如 p53）进行蛋白酶体降解，促进肿瘤形成。在这项研究中，筛选出抗感染药物硝呋莫司（NXQ），通过抑制抗凋亡蛋白（如 Bcl-2 和 MCL1）和上调促凋亡蛋白 Bim，有效抑制小细胞肺癌（SCLC）细胞的存活，并诱导 SCLC 细胞凋亡。在机制研究中，发现 NXQ 通过诱导 MDM2 的蛋白酶体降解而下调 MDM2 表达，从而上调 p53 表达，p53 是 MDM2 的底物蛋白。此外，MDM2 的过表达降低了 NXQ 对 SCLC 细胞的细胞毒性。这些结果表明，NXQ 通过抑制 MDM2 表达显示出抗 SCLC 活性，这表明抗感染 NXQ 通过靶向 MDM2/p53 轴具有治疗 SCLC 的潜力。
