ACSL3 regulates lipid droplet biogenesis and ferroptosis sensitivity in clear cell renal cell carcinoma.
ACSL3 regulates lipid droplet biogenesis and ferroptosis sensitivity in clear cell renal cell carcinoma.
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DOI：
10.1186/s40170-022-00290-z
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发表时间：
2022-10-03
影响因子：
5.9
通讯作者：
中科院分区：
文献类型：
--
作者：
透明细胞肾细胞癌（ccRCC）是肾癌的主要亚型，具有多种代谢途径的特征性改变，包括细胞溶质脂滴的积聚。然而，驱动脂滴在ccRCC细胞中积累的途径及其对癌症生物学的重要性仍然知之甚少。我们试图通过油红O染色和同位素示踪脂质组学来确定脂滴积累所需的碳源。利用siRNA和药物介导的抑制研究了脂代谢酶中重要的一组酰基辅酶A合成酶（ACSL）家族成员的作用。进行CTB和XTT测定以确定ACSL 3敲低和脂质饥饿对ccRCC细胞活力的影响，并使用shRNA研究ACSL 3在原位小鼠模型中的影响。使用基于CTB和FACS的测定来检查ccRCC的铁凋亡易感性与ACSL 3控制的脂质代谢之间的关系。用XTT存活测定显示了5-LOX在ccRCC中的铁凋亡易感性中的重要性，并评估了TCGA ccRCC数据中5-LOX的表达水平和预测值。我们发现，ccRCC细胞通过代谢外源性血清衍生的脂质而不是通过从头脂肪生成来获得脂滴积累所需的底物。我们表明，这种外源性脂肪酸代谢成脂滴需要酶酰基辅酶A合成酶3（ACSL 3），而不是其他ACSL家族蛋白。重要的是，ACSL 3的遗传或药理学抑制在体外对ccRCC细胞具有细胞毒性，并导致原位小鼠模型中肿瘤重量减轻。相反，ACSL 3抑制降低了ccRCC细胞对铁凋亡的易感性，铁凋亡是一种涉及脂质过氧化的非凋亡形式的细胞死亡。ccRCC对铁凋亡的敏感性也高度依赖于外源性脂肪酸的组成和5-脂氧合酶（5-LOX），5-脂氧合酶是一种产生白三烯的酶，其产生与其他癌症有关但与ccRCC无关的脂质过氧化物。ACSL 3调节脂滴在ccRCC中的积累，并且对于肿瘤生长是必需的。此外，ACSL 3还以依赖于外源性脂肪酸组成的方式调节铁凋亡敏感性。ACSL 3的两种功能都可以用于ccRCC治疗。在线版本包含补充材料，可通过10.1186/s40170-022-00290-z获得。
Clear cell renal cell carcinoma (ccRCC), the predominant subtype of kidney cancer, possesses characteristic alterations to multiple metabolic pathways, including the accumulation of cytosolic lipid droplets. However, the pathways that drive lipid droplet accumulation in ccRCC cells and their importance to cancer biology remain poorly understood. We sought to identify the carbon sources necessary for lipid droplet accumulation using Oil red O staining and isotope-tracing lipidomics. The role of the acyl-CoA synthetase (ACSL) family members, an important group of lipid metabolic enzymes, was investigated using siRNA and drug mediated inhibition. CTB and XTT assays were performed to determine the effect of ACSL3 knockdown and lipid starvation on ccRCC cell viability and shRNA was used to study the effect of ACSL3 in an orthotopic mouse model. The relationship between ferroptosis susceptibility of ccRCC and ACSL3 controlled lipid metabolism was examined using CTB and FACS-based assays. The importance of 5-LOX in ferroptosis susceptibility in ccRCC was shown with XTT survival assays, and the expression level and predictive value of 5-LOX in TCGA ccRCC data was assessed. We found that ccRCC cells obtain the necessary substrates for lipid droplet accumulation by metabolizing exogenous serum derived lipids and not through de novo lipogenesis. We show that this metabolism of exogenous fatty acids into lipid droplets requires the enzyme acyl-CoA synthetase 3 (ACSL3) and not other ACSL family proteins. Importantly, genetic or pharmacologic suppression of ACSL3 is cytotoxic to ccRCC cells in vitro and causes a reduction of tumor weight in an orthotopic mouse model. Conversely, ACSL3 inhibition decreases the susceptibility of ccRCC cells to ferroptosis, a non-apoptotic form of cell death involving lipid peroxidation. The sensitivity of ccRCC to ferroptosis is also highly dependent on the composition of exogenous fatty acids and on 5-lipoxygenase (5-LOX), a leukotriene producing enzyme which produces lipid peroxides that have been implicated in other cancers but not in ccRCC. ACSL3 regulates the accumulation of lipid droplets in ccRCC and is essential for tumor growth. In addition, ACSL3 also modulates ferroptosis sensitivity in a manner dependent on the composition of exogenous fatty acids. Both functions of ACSL3 could be exploited for ccRCC therapy. The online version contains supplementary material available at 10.1186/s40170-022-00290-z.
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ACSL4 通过塑造细胞脂质成分来决定铁死亡敏感性。
影响因子：
14.8
作者：
Doll S;Proneth B;Tyurina YY;Panzilius E;Kobayashi S;Ingold I;Irmler M;Beckers J;Aichler M;Walch A;Prokisch H;Trümbach D;Mao G;Qu F;Bayir H;Füllekrug J;Scheel CH;Wurst W;Schick JA;Kagan VE;Angeli JP;Conrad M
通讯作者：
Conrad M
影响因子：
14.8
作者：
Kagan VE;Mao G;Qu F;Angeli JP;Doll S;Croix CS;Dar HH;Liu B;Tyurin VA;Ritov VB;Kapralov AA;Amoscato AA;Jiang J;Anthonymuthu T;Mohammadyani D;Yang Q;Proneth B;Klein-Seetharaman J;Watkins S;Bahar I;Greenberger J;Mallampalli RK;Stockwell BR;Tyurina YY;Conrad M;Bayır H
通讯作者：
Bayır H
影响因子：
64.5
作者：
Dixon SJ;Lemberg KM;Lamprecht MR;Skouta R;Zaitsev EM;Gleason CE;Patel DN;Bauer AJ;Cantley AM;Yang WS;Morrison B 3rd;Stockwell BR
通讯作者：
Stockwell BR
影响因子：
4.8
作者：
Cockman, ME;Masson, N;Maxwell, PH
通讯作者：
Maxwell, PH
影响因子：
64.8
作者：
Maxwell, PH;Wiesener, MS;Ratcliffe, PJ
通讯作者：
Ratcliffe, PJ