MAT2A-ACSL3 通路的激活可保护胃癌细胞免受铁死亡。
Activation of MAT2A-ACSL3 pathway protects cells from ferroptosis in gastric cancer.
机构信息
Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Central Laboratory, The First Affiliated Hospital of Wannan Medical College (Yijishan Hospital of Wannan Medical College), Wuhu, China; Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Department of Gastric Surgery, Fudan University Shanghai Cancer Center, Shanghai, China; Key Laboratory of Non-coding RNA Transformation Research of Anhui Higher Education Institution, Wannan Medical College, Wuhu, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
出版信息
Free Radic Biol Med. 2022 Mar;181:288-299. doi: 10.1016/j.freeradbiomed.2022.02.015. Epub 2022 Feb 16.
BACKGROUND
Ferroptosis, a unique form of nonapoptotic-regulated cell death caused by overwhelming lipid peroxidation, represents an emerging tumor suppression mechanism. Growing evidence has demonstrated that cell metabolism plays an important role in the regulation of ferroptosis. Specifically, the association between methionine metabolism and ferroptosis remains undefined.
METHODS
We performed in vitro and in vivo experiments to evaluate the influence of methionine metabolism on ferroptosis sensitivity. Pharmacological and genetic blockade of the methionine cycle was utilized and relevant molecular analyses were performed.
RESULTS
We identified MAT2A as a driver of ferroptosis resistance. Mechanistically, MAT2A mediates the production of S-adenosylmethionine (SAM), which upregulates ACSL3 by increasing the trimethylation of lysine-4 on histone H3 (H3K4me3) at the promoter area, resulting in ferroptosis resistance.
CONCLUSIONS
Collectively, these results established a link between methionine cycle activity and ferroptosis vulnerability in gastric cancer.
背景
铁死亡是一种由脂质过氧化引起的独特的非凋亡性调控细胞死亡形式，代表了一种新兴的肿瘤抑制机制。越来越多的证据表明，细胞代谢在铁死亡的调控中起着重要作用。具体来说，蛋氨酸代谢与铁死亡之间的关联尚不清楚。
方法
我们进行了体外和体内实验，以评估蛋氨酸代谢对铁死亡敏感性的影响。我们利用蛋氨酸循环的药理学和遗传学阻断，并进行了相关的分子分析。
结果
我们确定 MAT2A 是铁死亡抵抗的驱动因素。从机制上讲，MAT2A 介导 S-腺苷甲硫氨酸（SAM）的产生，通过增加组蛋白 H3 赖氨酸-4 上的三甲基化（H3K4me3）来上调 ACSL3，从而促进铁死亡抵抗。
结论
总的来说，这些结果在胃癌中建立了蛋氨酸循环活性与铁死亡易感性之间的联系。
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