Triggering a New Cancer Cell Death Mechanism in Sarcoma

项目摘要 致命的小分子是发现和表征新的细胞死亡的强大工具 可能对癌症治疗有用的机制。使用小分子，我们已经识别出 一种非常规形式的非凋亡性细胞死亡，不同于凋亡、铁下垂、 以及其他已知的细胞死亡形式。这种致死机制需要蛋白质棕榈酰化和 涉及到蛋白质运输的中断。在这项研究中，我们建议测试脂质的作用 可以积极或消极地调节手掌下垂的代谢酶。这样做的一个目的是 研究将集中在脂代谢酶TECR(反式-2，3-烯-辅酶A还原酶)。我们 将测试TECR合成棕榈酸酯的假设，棕榈酸酯是蛋白质棕榈酰化所使用的 通过改变蛋白质运输来驱动细胞死亡的酶。这项研究的第二个目的是测试 假设细胞死亡是由磷脂酰胆碱代谢中断引发的， 这改变了蛋白质的交易。这项研究的第三个目标将检验这样一个假设，即这个新的 在基因工程小鼠癌症模型中，细胞死亡机制可以通过一种 临床候选药物。虽然这种细胞死亡机制可以在不同的癌症中激活，但 建议研究的主要焦点是肉瘤，肉瘤对这种致命的疾病高度敏感。 机制，迫切需要新的治疗方法。总而言之，这些研究将 定义一种新的细胞死亡形式和可能被利用的相关生化机制 用于治疗肉瘤和其他癌症。

Project Abstract Lethal small molecules are powerful tools to discover and characterize new cell death mechanisms that may be useful for cancer treatment. Using small molecules, we have identified an unconventional form of non-apoptotic cell death that is distinct from apoptosis, ferroptosis, and other known forms of cell death. This lethal mechanism requires protein palmitoylation and involves the disruption of protein trafficking. In this research we propose to test the role of lipid metabolic enzymes that may positively or negatively regulate palmoptosis. One Aim of this research will focus on the lipid metabolic enzyme TECR (trans-2,3-enoyl-CoA reductase). We will test the hypothesis that TECR synthesizes palmitate that is used by protein palmitoylation enzymes to drive cell death via altered protein trafficking. A second Aim of this research will test the hypothesis that cell death is triggered by the disruption of phosphatidylcholine metabolism, which alters protein trafficking. A third Aim of this research will test the hypothesis that this new cell death mechanism can be activated in genetically engineered mouse models of cancer by a clinical drug candidate. While this cell death mechanism can be activated in diverse cancers, a major focus of the proposed studies is on sarcoma, which is highly sensitive to this lethal mechanism and for which new treatments are urgently needed. Together, these studies will define a new form of cell death and associated biochemical mechanisms that may be exploited for the treatment of sarcoma and other cancers.