The role of membrane lipid remodeling in cancer cell ferroptosis sensitivity

膜脂重塑在癌细胞铁死亡敏感性中的作用

• 批准号: 10315803
• 负责人: Jason Rodencal
• 金额: $ 3.85万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2023-12-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10315803
• 关键词: Acyltransferase; Address; Affect; Antineoplastic Agents; Antioxidants; Biological; C-terminal; CDK4 gene; Cancer Biology; Cancer Patient; Cell Death; Cell membrane; Cells; Cessation of life; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Development; Disease; Drug Targeting; Endoplasmic Reticulum; Enzymes; Gene Expression; Genes; Goals; In Vitro; Knowledge; Lead; Life; Link; Lipids; Malignant Neoplasms; Malignant neoplasm of pancreas; Measures; Membrane; Membrane Lipids; Mentors; Metabolic; Metabolism; Monounsaturated Fatty Acids; Mus; Organelles; Oxides; Pharmacology; Phospholipid Metabolism; Phospholipids; Plasmalogens; Polyunsaturated Fatty Acids; Predisposition; Prognosis; Proteins; Reactive Oxygen Species; Regulation; Role; Scientist; Tail; Testing; Training; Work; base; cancer cell; cancer therapy; cancer type; clinical candidate; clinically significant; experience; experimental study; in vivo; inhibitor/antagonist; lipid metabolism; lipidome; mutant; neoplastic cell; novel; novel strategies; pancreatic cancer patients; peroxidation; pi bond; reconstitution; skills; targeted cancer therapy; therapy resistant; tumor; tumor xenograft

Project Summary Phospholipids are the major component of biological membranes and are essential for all cellular life. Phospholipid metabolism is altered in tumor cells. However, there are currently no approved anti-cancer drugs that target phospholipid metabolic enzymes. Inhibition of survival-promoting phospholipid metabolic enzymes would present a novel strategy to induce cell death in cancer cells. Ferroptosis is a form of cell death that is dependent on membrane phospholipid composition. Ferroptosis is caused by direct damage to membrane phospholipids by reactive oxygen species (ROS). Our group and others have found that the tail groups of phospholipids can determine a cell’s sensitivity to ferroptosis. Tail groups with multiple double-bonds (polyunsaturated fatty acids, PUFAs) are more likely to be oxidized than those with only one double bond (monounsaturated fatty acid, MUFA). Therefore, cells with greater levels of PUFAs are more susceptible to death by ferroptosis, whereas cells with greater levels of MUFAs resist ferroptosis. This is particularly relevant in cancer treatment because induction of ferroptosis is emerging as an effective strategy to kill cancer cells. In preliminary studies, I find that Membrane-Bound O-Acyltransferase 1 (MBOAT1) is a novel ferroptosis regulating gene. MBOAT1 is a lipid metabolic gene that incorporates MUFAs into phospholipids. MBOAT1 gene expression or copy number is elevated in multiple tumor types, and higher expression of MBOAT1 is correlated with poor prognosis in pancreatic cancer patients. I find that inhibiting MBOAT1 increases cancer cells’ susceptibility to ferroptosis. Therefore, MBOAT1 represents a novel target for cancer treatment. Based on these findings, I hypothesize that inhibition of MBOAT1 sensitizes cells to ferroptosis by altering phospholipid metabolism. In Aim 1, I will elucidate the role of MBOAT1 in ferroptosis sensitivity and in phospholipid metabolism. Then in Aim 2, I will test the combination of MBOAT1 inhibition and ferroptosis induction as a novel strategy for the treatment of cancer in vivo. Overall, this work will have biological significance by characterizing the function and regulation of MBOAT1, and clinical significance by establishing MBOAT1 as a novel target to induce ferroptosis in cancer cells.

项目摘要 磷脂是生物膜的主要成分，对所有细胞生命都是必不可少的。 磷脂代谢在肿瘤细胞中改变。不过，目前还没有获批的抗癌药物 以磷脂代谢酶为目标。抑制促进存活的磷脂代谢酶 将提出一种诱导癌细胞死亡的新策略。铁凋亡是一种细胞死亡的形式， 取决于膜磷脂组成。亚铁凋亡是由膜直接损伤引起的 活性氧（ROS）的磷脂。我们的团队和其他人发现， 磷脂可以决定细胞对铁凋亡的敏感性。多双键尾基 （多不饱和脂肪酸，PUFA）比那些只有一个双键的更容易被氧化 （单不饱和脂肪酸，MUFA）。因此，PUFA水平较高的细胞更容易死亡 而具有较高水平MUFA的细胞抵抗铁凋亡。这一点在癌症中尤为重要 治疗，因为铁凋亡的诱导正在成为杀死癌细胞的有效策略。初步 研究发现膜结合O-酰基转移酶1（MBOAT 1）是一个新的铁凋亡调控基因。 MBOAT 1是一个脂质代谢基因，它将MUFA掺入磷脂中。MBOAT 1基因表达或 拷贝数在多种肿瘤类型中升高，并且MBOAT 1的高表达与低表达相关。 胰腺癌患者的预后。我发现抑制MBOAT 1会增加癌细胞对 铁性下垂因此，MBOAT 1代表了癌症治疗的新靶点。基于这些发现，我 假设MBOAT 1抑制通过改变磷脂使细胞对铁凋亡敏感 新陈代谢.在目的1中，我将阐明MBOAT 1在铁凋亡敏感性和磷脂酰胆碱（LPA）中的作用。 新陈代谢.然后在目标2中，我将测试MBOAT 1抑制和铁凋亡诱导的组合作为一种新的方法。 在体内治疗癌症的策略。总的来说，这项工作将具有生物学意义， MBOAT 1的功能和调节，以及通过建立MBOAT 1作为新靶点， 在癌细胞中诱导铁凋亡。