Targeting Mitochondrial Proline Dehydrogenase with a Suicide Inhibitor to Exploit Synthetic Lethal Interactions with p53 Upregulation and Glutaminase Inhibition
Targeting Mitochondrial Proline Dehydrogenase with a Suicide Inhibitor to Exploit Synthetic Lethal Interactions with p53 Upregulation and Glutaminase Inhibition
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DOI：
10.1158/1535-7163.mct-18-1323
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发表时间：
2019-08-01
影响因子：
5.7
通讯作者：
Benz, Christopher C.
中科院分区：
文献类型：
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作者：
Scott, Gary K.;Yau, Christina;Benz, Christopher C.
脯氨酸脱氢酶 (PRODH) 是一种 p53 诱导型线粒体内膜黄素蛋白，与回补谷氨酸和 ATP 生成的电子传递相关，这对于微环境应激条件下癌细胞的生存至关重要。提出 PRODH 是一种独特的线粒体癌症靶标，我们对其癌细胞活性进行了结构建模并比较了暴露于可逆（S-5-oxo：S-5-oxo-2-四氢呋喃甲酸）或不可逆（N-PPG：N-炔丙基甘氨酸）PRODH 抑制剂时的后果。与 5-oxo 不同，自杀抑制剂 N-PPG 诱导 PRODH 蛋白的早期选择性衰变，而不触发线粒体破坏，这与 N-PPG 激活线粒体未折叠蛋白反应一致。果蝇和乳腺肿瘤 (MCF7) 异种移植小鼠研究表明，足以表型复制 PRODH 敲除并诱导其衰变的 N-PPG 剂量可以在体内安全有效地施用。在乳腺癌细胞系和肿瘤样本中，PRODH mRNA 表达具有亚型依赖性，并且与谷氨酰胺酶 (GLS1) 表达呈负相关； PRODH（S-5-oxo 和 N-PPG）和 GLS1（CB-839）抑制剂的组合即使不是协同作用，也会导致癌细胞（ZR-75-1、MCF7、DU4475 和 BT474）生长和活力的损失。虽然单独敲低 PRODH 可以诱导癌细胞凋亡，但当 MDM2 拮抗剂（MI-63 和 nutlin-3）同时上调 p53 时，可逆或不可逆 PRODH 抑制剂的抗癌潜力会大大增强。然而，当 PRODH 自杀抑制剂 N-PPG 与 GLS1 抑制剂和 p53 上调 MDM2 拮抗剂联合使用时，在体外观察到最大的抗癌协同作用。这些发现为开发 N-PPG 样 PRODH 抑制剂作为癌症治疗药物以利用与 p53 上调和 GLS1 抑制的合成致死相互作用提供了临床前理论依据。
Proline dehydrogenase (PRODH) is a p53-inducible inner mitochondrial membrane flavoprotein linked to electron transport for anaplerotic glutamate and ATP production, most critical for cancer cell survival under microenvironmental stress conditions. Proposing that PRODH is a unique mitochondrial cancer target, we structurally model and compare its cancer cell activity and consequences upon exposure to either a reversible (S-5-oxo: S-5-oxo-2-tetrahydrofurancarboxylic acid) or irreversible (N-PPG: N-propargylglycine) PRODH inhibitor. Unlike 5-oxo, the suicide inhibitor N-PPG induces early and selective decay of PRODH protein without triggering mitochondrial destruction, consistent with N-PPG activation of the mitochondrial unfolded protein response. Fly and breast tumor (MCF7)-xenografted mouse studies indicate that N-PPG doses sufficient to phenocopy PRODH knockout and induce its decay can be safely and effectively administered in vivo. Among breast cancer cell lines and tumor samples, PRODH mRNA expression is subtype dependent and inversely correlated with glutaminase (GLS1) expression; combining inhibitors of PRODH (S-5-oxo and N-PPG) and GLS1 (CB-839) produces additive if not synergistic loss of cancer cell (ZR-75-1, MCF7, DU4475, and BT474) growth and viability. Although PRODH knockdown alone can induce cancer cell apoptosis, the anticancer potential of either reversible or irreversible PRODH inhibitors is strongly enhanced when p53 is simultaneously upregulated by an MDM2 antagonist (MI-63 and nutlin-3). However, maximum anticancer synergy is observed in vitro when the PRODH suicide inhibitor, N-PPG, is combined with both GLS1-inhibiting and a p53-upregulating MDM2 antagonist. These findings provide preclinical rationale for the development of N-PPG-like PRODH inhibitors as cancer therapeutics to exploit synthetic lethal interactions with p53 upregulation and GLS1 inhibition.