Lipid metabolism offers anticancer treatment by regulating ferroptosis.
Lipid metabolism offers anticancer treatment by regulating ferroptosis.
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脂质代谢通过调节铁死亡提供抗癌治疗。
DOI：
10.1038/s41418-019-0418-2
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发表时间：
2019
影响因子：
12.4
通讯作者：
Carbone M
中科院分区：
文献类型：
--
作者：
Carbone M
了解肿瘤进展的分子机制对于开发创新疗法至关重要。最初的代谢变化发生在恶性细胞转化的过程中。随后，肿瘤细胞适应其代谢活动，以响应从局部微增殖到转移的整个癌症进展过程中发生的微环境变化。糖酵解、能量产生和脂质代谢适应在癌细胞与微环境中存在的其他细胞类型之间以及癌细胞与治疗药物之间发生的相互作用中起关键作用。癌细胞代谢和形成肿瘤微环境、巨噬细胞、肿瘤浸润淋巴细胞、内皮细胞和成纤维细胞的各种细胞类型的代谢都是相互关联的，因此相互影响。此外，当地的营养物质和氧气浓度的可用性显着改变景观。例如，在较低的氧气压力下，转录因子缺氧诱导因子1 α（HIF）在过氧化物酶体中不被羟基化和降解;相反，HIF跨核膜易位并激活调节糖酵解、细胞毒性、转录和肿瘤细胞生长的基因的表达。事实上，虽然初始或静止的T细胞主要通过高效产生ATP的线粒体氧化磷酸化来满足其生物能量需求，（产生34个ATP净分子的Kreb循环），T细胞活化的特征是能量产生向效率较低但更快的有氧糖酵解转变在某些实施方案中，抗肿瘤效应是一种免疫抑制剂（瓦尔堡效应），其仅产生两个ATP分子，并且随着时间的推移导致T细胞耗竭，以及随之而来的进行性免疫功能障碍，其中T细胞增殖减少、细胞因子产生减少和抗肿瘤效应物能力降低。T细胞耗竭降低了肿瘤与T细胞的相互作用（由pMHC/TCR、LAG 3以及PD-L1/2和PD-1介导），从而降低了免疫细胞对抗癌细胞的总体能力。因此，肿瘤免疫微环境（TIME）是一个高度复杂的网络，代谢在其中发挥着至关重要的作用，尽管仍有部分未被探索。异常的血管功能、间充质基质细胞和干细胞、免疫活性细胞和脂质介导的能量都可以调节缺氧限制的药物分布及其药代动力学。关于铁凋亡作用和脂质代谢在TIME中的作用的最新进展，包括更好地理解固醇辅酶A去饱和酶（SCD 1）[1]，揭示了脂质代谢如何与铁凋亡的激活结合，可能表明一种使用SCD 1抑制剂与铁凋亡诱导剂组合开发新型组合治疗方法的方法。Δ9-脂肪酰基-CoA去饱和酶，EC：1.14。19.1，也称为硬脂酰-CoA-去饱和酶，需要来自细胞色素b5的电子（以还原形式）以及O2，以便将双键插入饱和脂肪酰基-CoA底物中以从饱和脂肪酸产生单不饱和脂肪酸，参见图1a，其进而用于产生二酰基甘油、胆固醇酯、蜡酯、磷脂以及甘油三酯，都是细胞膜的主要组成部分如上文和图la中所示，该酶催化在位置δ-9处的顺式双键形成为脂肪酰基-CoA底物，包括硬脂酰基-CoA和棕榈酰基-CoA，并因此产生16：1和18：1不饱和脂肪酸。
Understanding the molecular mechanisms underlying tumour progression is crucial for developing innovative therapies. Initial metabolic changes occur during the process of malignant cell transformation. Subsequently, neoplastic cells adapt their metabolic activities in response to microenvironmental changes occurring throughout cancer progression, from local micro-proliferation to metastasis. Glycolysis, energy production and lipid metabolic adaptation play a crucial role in the interactions that take place between cancer cells and the other cell types present in the microenvironment and between cancer cells and therapeutic drugs. Cancer cell metabolism and the metabolism of the various cell types that form the tumour microenvironment, macrophages, tumour-infiltrating lymphocytes, endothelial cells, and fibroblasts, are all inter-related and thus influence each others activities. Moreover, the local availability of nutrients and oxygen concentration alters the landscape significantly. For example, at lower oxygen pressure, the transcription factor Hypoxia-Inducible Factor 1 alpha (HIF) is not hydroxylated and degraded in the peroxisome; instead HIF translocates across the nuclear membrane and activates expression of genes that regulated glycolysis, cytotoxicity, transcription, and tumour cell growth. Indeed, while naive or quiescent T cells meet their bioenergetic needs primarily via the highly efficient ATP-producing mitochondrial oxidative phosphorylation (Kreb’s cycle that produces 34 net molecules of ATP), T-cell activation is characterised by a shift in energy production to the less efficient but much more rapid aerobic glycolysis (Warburg effect) that produces only two molecules of ATP, and that over time leads to T-cell exhaustion, and consequent progressive immunologic dysfunction with reduced T-cell proliferation, cytokine production, and diminished antitumor effector capacity. T-cell exhaustion reduces tumour interaction with T cells (mediated by pMHC/TCR, by LAG3 and by PD-L1/2 and PD-1) and thus the overall ability of immune cells to fight cancer cells. The Tumour Immune Micro-Environment (TIME) is therefore a highly complex network where metabolism plays a crucial although still partially unexplored, role. Abnormal vascular function, mesenchymal stromal and stem cells, immune-competent cells and lipid-mediated energy, can both modulate hypoxia-restricted drug distribution and its pharmacokinetics. Recent advances on the role of ferroptosis and on the role of lipid metabolism in the TIME, including a better understanding of steroyl CoA desaturase (SCD1)[1] has revealed how lipid metabolism in conjunction with the activation of ferroptosis, may suggest a way to develop novel combinatorial therapeutic approaches using SCD1 inhibitors in combination with ferroptosis inducers. Δ9-fatty acyl-CoA desaturase, EC: 1.14. 19.1, also known as Stearoyl-CoA-desaturase, requires electrons from cytochrome b5 (in the reduced form) as well as O2 in order to insert a double bond into saturated fatty acyl-CoA substrates to produce monounsaturated fatty acids from saturated fatty acids, see Fig. 1 a, which in turn are used to produce diacylglycerols, cholesterol esters, wax esters, phospholipids, as well as triglycerides, all major component of cellular membranes. This enzyme, as indicated above and in Fig. 1 a, catalyses the formation of a cis double bond in position delta-9 into fatty acyl-CoA substrates including stearoyl-CoA and palmitoyl-CoA and therefore produces both 16: 1 and 18: 1 unsaturated fatty