Modulation of ferroptosis sensitivity by altered lipid metabolism in cancer

通过改变癌症中的脂质代谢来调节铁死亡敏感性

• 批准号: 461705295
• 负责人: Professorin Dr. Almut Schulze
• 金额: --
• 依托单位: Abteilung Tumor Metabolismus und Microenvironment
• 依托单位国家: 德国
• 项目类别: Priority Programmes
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/461705295?language=en
• 关键词: Modulation; ferroptosis; sensitivity; altered; lipid

Ferroptosis has recently emerged as a novel mechanism of programmed cell death that is mechanistically connected to the accumulation of hydroperoxides in membrane lipids that contain poly-unsaturated fatty acids (PUFA). Accumulation of such lipid peroxides causes destabilisation of the lipid bilayer, leading to enhanced membrane permeability and ultimately cell death. To counteract lipid damage, cells have evolved several mechanisms that eliminate lipid peroxides by turning them into alcohols. One of these mechanisms involves the glutathione peroxidase 4 (GPX4), which uses reduced glutathione (GSH) as a cofactor. Another mechanism requires the ferroptosis suppressor protein 1 (FSP1), a oxidoreductase that is localised to the plasma membrane where it recycles ubiquinol to maintain its anti-oxidant function. Moreover, it has bene shown that mono-unsaturated fatty acids (MUFA) also prevent excess lipid peroxidation, thereby reducing the sensitivity of cells towards ferroptosis. Ferroptosis plays an important role in cancer, as oncogene activation of loss of tumour suppressor function drives oxidative stress that leads to enhanced lipid peroxidation. At the same time, oxidative metabolism of PUFA-containing lipids is also required to drive the production of lipid mediators that promote migration, angiogenesis and immune evasion in cancer. It is therefore important that cancer cells maintain the activity of processes that counteract excess lipid peroxidation and prevent ferroptosis. Consequently, targeting these processes could be promising strategies for cancer treatment. In this project, we will investigate the role of fatty acid desaturases responsible for the synthesis of different MUFA and PUFA species in defining ferroptosis susceptibility in cancer cells. We will investigate the effect of modulating the expression of these desaturases on cellular lipid composition and ferroptosis sensitivity. In order to provide physiological levels of essential metabolites, experiments will be conducted in specially formulated media that resemble the metabolite composition of plasma and interstitial fluids from different organs to create in vivo-like metabolic niches. We will also use a mouse model of liver cancer to characterise changes in lipid metabolism and anti-ferroptotic mechanisms during tumourigenesis. Finally, we will investigate whether perturbation of fatty acid desaturation pathways or the GSH/GPX4 axis blocks tumour growth in a preclinical model to evaluate whether induction of ferroptosis could be a therapeutic strategy.

铁凋亡最近已成为程序性细胞死亡的一种新机制，其与含有多不饱和脂肪酸（PUFA）的膜脂质中氢过氧化物的积累有关。这种脂质过氧化物的积累导致脂质双层的不稳定，导致膜渗透性增强并最终导致细胞死亡。为了对抗脂质损伤，细胞已经进化出几种机制，通过将脂质过氧化物转化为醇来消除脂质过氧化物。这些机制之一涉及谷胱甘肽过氧化物酶4（GPX 4），它使用还原型谷胱甘肽（GSH）作为辅因子。另一种机制需要铁凋亡抑制蛋白1（FSP 1），这是一种定位于质膜的氧化还原酶，在质膜上它分解泛醇以维持其抗氧化功能。此外，已经证明单不饱和脂肪酸（MUFA）还防止过度的脂质过氧化，从而降低细胞对铁凋亡的敏感性。铁凋亡在癌症中起着重要作用，因为肿瘤抑制功能丧失的癌基因激活驱动氧化应激，导致脂质过氧化作用增强。同时，含PUFA的脂质的氧化代谢也需要驱动脂质介质的产生，这些脂质介质促进癌症中的迁移、血管生成和免疫逃避。因此，重要的是，癌细胞保持抵抗过量脂质过氧化和防止铁凋亡的过程的活性。因此，靶向这些过程可能是癌症治疗的有前途的策略。 在这个项目中，我们将调查的作用，脂肪酸去饱和酶负责合成不同的MUFA和PUFA物种在定义铁凋亡易感性的癌细胞。我们将研究调节这些去饱和酶的表达对细胞脂质组成和铁凋亡敏感性的影响。为了提供生理水平的必需代谢物，将在与来自不同器官的血浆和间质液的代谢物组成相似的特殊配制培养基中进行实验，以创建体内样代谢小生境。我们还将使用小鼠肝癌模型来研究肿瘤发生过程中脂质代谢和抗铁蛋白代谢机制的变化。最后，我们将研究是否干扰脂肪酸去饱和途径或GSH/GPX 4轴阻断肿瘤生长的临床前模型，以评估是否诱导铁凋亡可能是一种治疗策略。