Cold Spring Harbor Laboratory, Cancer Biology, Cold Spring Harbor, NY, USA.
Northwestern Medical School, Cell and Molecular Biology, Chicago, IL, USA.
Cell Rep. 2018 Apr 3;23(1):58-67. doi: 10.1016/j.celrep.2018.03.032.
A hallmark of advanced prostate cancer (PC) is the concomitant loss of PTEN and p53 function. To selectively eliminate such cells, we screened cytotoxic compounds on Pten;Trp53 fibroblasts and their Pten-WT reference. Highly selective killing of Pten-null cells can be achieved by deguelin, a natural insecticide. Deguelin eliminates Pten-deficient cells through inhibition of mitochondrial complex I (CI). Five hundred-fold higher drug doses are needed to obtain the same killing of Pten-WT cells, even though deguelin blocks their electron transport chain equally well. Selectivity arises because mitochondria of Pten-null cells consume ATP through complex V, instead of producing it. The resulting glucose dependency can be exploited to selectively kill Pten-null cells with clinically relevant CI inhibitors, especially if they are lipophilic. In vivo, deguelin suppressed disease in our genetically engineered mouse model for metastatic PC. Our data thus introduce a vulnerability for highly selective targeting of incurable PC with inhibitors of CI.
晚期前列腺癌（PC）的一个标志是同时丧失 PTEN 和 p53 功能。为了选择性地消除这些细胞，我们在 Pten;Trp53 成纤维细胞及其 Pten-WT 对照物上筛选细胞毒性化合物。天然杀虫剂 deguelin 可高度选择性地杀死 Pten 缺失细胞。通过抑制线粒体复合物 I（CI），deguelin 消除 Pten 缺陷细胞。尽管 deguelin 同样有效地阻断 Pten-WT 细胞的电子传递链，但需要高 500 倍的药物剂量才能获得相同的杀伤效果。选择性源于 Pten 缺失细胞的线粒体通过复合物 V 消耗 ATP，而不是产生它。由此产生的葡萄糖依赖性可用于用临床相关的 CI 抑制剂选择性地杀死 Pten 缺失细胞，尤其是如果它们是亲脂性的。在体内，deguelin 抑制了我们用于转移性 PC 的基因工程小鼠模型中的疾病。因此，我们的数据为使用 CI 抑制剂高度选择性地靶向无法治愈的 PC 提供了一个脆弱性。
