Roberts Lindsay S, Yan Peter, Bateman Leslie A, Nomura Daniel K
Departments of Chemistry, Molecular and Cell Biology, and Nutritional Sciences and Toxicology, 127 Morgan Hall, University of California, Berkeley , Berkeley, California 94720, United States.
ACS Chem Biol. 2017 Apr 21;12(4):1133-1140. doi: 10.1021/acschembio.6b01159. Epub 2017 Mar 8.
Triple-negative breast cancers (TNBCs) are estrogen receptor, progesterone receptor, and HER2 receptor-negative subtypes of breast cancers that show the worst prognoses and lack targeted therapies. Here, we have coupled the screening of ∼400 anticancer agents that are under development or in the clinic with chemoproteomic and metabolomic profiling to identify novel metabolic mechanisms for agents that impair TNBC pathogenicity. We identify 20 anticancer compounds that significantly impaired cell survival across multiple types of TNBC cells. Among these 20 leads, the phytoestrogenic natural product licochalcone A was of interest, since TNBCs are unresponsive to estrogenic therapies, indicating that licochalcone A was likely acting through another target. Using chemoproteomic profiling approaches, we reveal that licochalcone A impairs TNBC pathogenicity, not through modulating estrogen receptor activity but rather through inhibiting prostaglandin reductase 1, a metabolic enzyme involved in leukotriene B4 inactivation. We also more broadly performed metabolomic profiling to map additional metabolic mechanisms of compounds that impair TNBC pathogenicity. Overlaying lipidomic profiling with drug responses, we find that deubiquitinase inhibitors cause dramatic elevations in acyl carnitine levels, which impair mitochondrial respiration and contribute to TNBC pathogenic impairments. We thus put forth two unique metabolic nodes that are targeted by drugs or drug candidates that impair TNBC pathogenicity. Our results also showcase the utility of coupling drug screens with chemoproteomic and metabolomic profiling to uncover unique metabolic drivers of TNBC pathogenicity.
三阴性乳腺癌（TNBC）是雌激素受体、孕激素受体和HER2受体均为阴性的乳腺癌亚型，其预后最差且缺乏靶向治疗方法。在此，我们将对约400种正在研发或已进入临床阶段的抗癌药物的筛选与化学蛋白质组学和代谢组学分析相结合，以确定能削弱TNBC致病性的药物的新代谢机制。我们鉴定出20种抗癌化合物，它们能显著损害多种类型TNBC细胞的存活。在这20种先导化合物中，植物雌激素类天然产物甘草查尔酮A引起了我们的兴趣，因为TNBC对雌激素疗法无反应，这表明甘草查尔酮A可能通过另一个靶点起作用。利用化学蛋白质组学分析方法，我们发现甘草查尔酮A削弱TNBC致病性，并非通过调节雌激素受体活性，而是通过抑制前列腺素还原酶1，这是一种参与白三烯B4失活的代谢酶。我们还更广泛地进行了代谢组学分析，以绘制能削弱TNBC致病性的化合物的其他代谢机制。将脂质组学分析与药物反应叠加，我们发现去泛素化酶抑制剂会导致酰基肉碱水平显著升高，这会损害线粒体呼吸并导致TNBC致病性受损。因此，我们提出了两个独特的代谢节点，它们是能削弱TNBC致病性的药物或候选药物的作用靶点。我们的研究结果还展示了将药物筛选与化学蛋白质组学和代谢组学分析相结合以揭示TNBC致病性独特代谢驱动因素的实用性。
