Targeting the detoxification function of the enzyme KDSR for cancer therapy

项目总结 人们越来越认识到，某些代谢酶在细胞中是必需的，而不是它们产生的东西， 而是用于加工，从而防止它们的底物积累，这可能具有毒性 属性。这类酶可以成为有吸引力的治疗靶点，因为它们的抑制作用会毒害癌细胞。 自身产生的有毒代谢物的方式高度依赖于有毒物质的产生 代谢物。在这里，我们研究了一种新的解毒酶，酮脱氢鞘氨酸还原酶(KDSR)， 这是神经鞘脂脂生物合成途径的一部分。我们发现KDSR不是必需的 提供鞘脂，因为癌细胞可以很容易地将它们从环境中拯救出来，但事实并非如此 以防止其底物3-酮脱氢鞘氨酸(3KDS)的积累。积累 3KDS通过KDSR KO或通过直接处理3KDS作用于细胞，似乎扰乱了内质 内质网(ER)，并导致癌细胞中错误折叠蛋白质的过载。这表明KDSR是一个 潜在的癌症治疗靶点能够损害癌细胞的内质网功能和蛋白稳定，这 我们将在这项提案中进行探索。在目标1中，我们将研究推动3KDS生产的上游步骤， 我们假设它在多种癌症亚型中升高，从而直接导致细胞 依赖KDSR进行3KDS解毒。这些将被进一步考虑为可能的生物标志物 对KDSR靶向有反应的肿瘤。在目标2中，我们将研究3KDS的积累如何扰乱 ER和导致死亡，以及癌细胞对3KDS毒性的反应。在AIM 3，我们将通过比较3KDS的生产能力来评估靶向KDSR的治疗潜力 来自动物模型的肿瘤组织和正常组织以及身份不明的患者组织之间的差异。在……里面 通过这种方式，我们希望为如何有选择地对子类型和 基于3KDS产生活动的癌细胞亚群提供了预测 肿瘤是否会对这样的治疗产生反应，并为内质网提供新的见解- 以及癌细胞与蛋白质平衡相关的脆弱性。

PROJECT SUMMARY It is increasingly recognized that certain metabolic enzymes are required in cells not for what they produce, but instead for processing and thus preventing the accumulation of their substrates which may have toxic properties. Such enzymes can be attractive therapeutic targets, as their inhibition can poison cancer cells with self-produced toxic metabolites in a manner that is highly dependent on production of the toxic metabolite. Here we investigate a new detoxifying enzyme, ketodehydrosphinganine reductase (KDSR), which is part of the de novo sphingolipid biosynthesis pathway. We find that KDSR is not required to provide sphingolipids, as cancer cells can readily salvage them from their environment, but instead is needed to prevent accumulation of its substrate 3-ketodehydrosphinganine (3KDS). Accumulation of 3KDS, either via KDSR KO or by direct treatment of 3KDS to cells, appears to disrupt the endoplasmic reticulum (ER) and cause an overload of misfolded proteins in cancer cells. This indicates KDSR as a potential cancer therapy target capable of impairing ER function and proteostasis in cancer cells, which we will explore in this proposal. In Aim 1, we will examine the upstream steps that drive 3KDS production, which we hypothesize are elevated in multiple cancer subtypes, and thus directly renders the cells dependent on KDSR for 3KDS detoxification. These will be further considered as possible biomarkers for tumors that would respond to KDSR targeting. In Aim 2, we will examine how 3KDS accumulation disrupts the ER and leads to death, and the responses mounted by cancer cells to counter 3KDS toxicity. In Aim 3, we will gauge the therapeutic potential of targeting KDSR by comparing 3KDS production capacity between tumor tissues and normal tissues from animal models and from deidentified patient tissues. In this manner we hope to provide a working blueprint for how to selectively target subtypes and subpopulation of cancer cells based on their 3KDS producing activities, provide biomarkers which predict whether a tumor will respond to such a therapy, and provide new insights into the endoplasmic reticulum- and proteostasis- related vulnerabilities of cancer cells.