Targeting metabolic stress to induce pancreatic tumor cell death

摘要 胰腺癌是一种毁灭性的疾病，五年存活率低于10%。其中一个主要因素是 突显这种低存活率的是缺乏有效的临床治疗。像大多数癌症一样，新陈代谢 胰腺癌细胞中的过程被改变以促进大分子的生物合成并防止 细胞内和细胞外应激源。活性氧种(ROS)是新陈代谢的副产物，代表着 对胰腺癌细胞来说是一种显著的代谢压力。之前，我们描述了一种新的代谢途径 胰腺癌，由胞浆谷氨酸草酰乙酸酯转氨酶1(GOT1)介导，用于 通过促进胞质和线粒体代谢的协调和维持来管理ROS 谷胱甘肽(GSH)池 铁下垂是最近被描述的一种铁依赖的、由脂质引起的非凋亡性细胞死亡。 过氧化和谷胱甘肽池的丧失介导的。我们发现，抑制GOT1增强了酶的活性 已知的铁眼药剂。此外，我们还发现，当结节时，GOT1抑制可以引起下垂。 半胱氨酸的代谢受到抑制。在这项研究计划中，我们将确定GOT1抑制如何 促进上睑下垂。来自这些研究的机械性洞察力将被用于选择性地靶向胰腺 癌症导致铁链细胞死亡。这将结合使用代谢组学技术来完成。 基因和新陈代谢的药物抑制剂。同时，我们将测试铁上剂的组合 在人类患者来源的3D培养模型和在原位小鼠模型中具有GOT1抑制的药物 确定转换值。鉴于GOT1和一些铁下垂诱导剂的安全性，深刻的 这种组合对胰腺癌细胞的敏感性，以及迫切需要新的治疗策略 胰腺癌，现在迫切需要从机制上了解是什么赋予了这些疾病的敏感性 组合。这样的见解可能会为促进胰腺癌氧化还原失衡提供策略，为 肿瘤选择性、以铁下垂为基础的治疗方法。

ABSTRACT Pancreatic cancer is a devastating disease with a five-year survival rate below 10%. One of the main factors underscoring this low survival rate is the lack of effective clinical treatments. Like most cancers, metabolic processes in pancreatic cancer cells are altered to facilitate macromolecular biosynthesis and protect against intra and extracellular stressors. Reactive oxygen species (ROS) are a byproduct of metabolism and represent a notable metabolic stress to pancreatic cancer cells. Previously, we described a new metabolic pathway in pancreatic cancer, mediated by cytosolic glutamate oxaloacetate transaminase 1 (GOT1), that is used to manage ROS by facilitating the coordination of cytosolic and mitochondrial metabolism and maintaining glutathione (GSH) pools. Ferroptosis is a recently described form of iron-dependent, non-apoptotic cell death caused by lipid peroxidation and mediated by loss of GSH pools. We found that GOT1 inhibition potentiated the activity of known ferroptotic agents. Further, we also discovered that GOT1 inhibition can engage ferroptosis when nodes in cysteine metabolism are inhibited. In this research proposal, we will determine how GOT1 inhibition promotes ferroptosis. Mechanistic insight from these studies will then be used to selectively target pancreatic cancers for ferroptotic cell death. This will be accomplished using metabolomics techniques in combination with genetic and pharmacological inhibitors of metabolism. In parallel, we will test combinations of ferroptotic agents with GOT1 inhibition in human patient-derived 3D culture models and in orthotopic mouse models to determine the translation value. Given the safety profile of GOT1 and some ferroptosis-inducers, the profound sensitivity of this combination in pancreatic cancer cells, and the desperate need for new strategies to treat pancreatic cancer, there is now a critical need to understand mechanistically what confers sensitivity to these combinations. Such insights may provide strategies to promote redox imbalance in pancreatic cancer, paving the way for tumor-selective, ferroptosis-based therapies.