S1PR3?G12-biased agonist ALESIA targets cancer metabolism and promotes glucose starvation
S1PR3?G12-biased agonist ALESIA targets cancer metabolism and promotes glucose starvation
复制标题
S1PR3？G12 偏向激动剂 ALESIA 靶向癌症代谢并促进葡萄糖饥饿
DOI：
10.1016/j.chembiol.2021.01.004
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发表时间：
2021
影响因子：
8.6
通讯作者：
Hagiwara Masatoshi
中科院分区：
文献类型：
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作者：
Toyomoto Masayasu;Inoue Asuka;Iida Kei;Denawa Masatsugu;Kii Isao;Ngako Kadji Francois Marie;Kishi Takayuki;Im Dohyun;Shimamura Tatsuro;Onogi Hiroshi;Yoshida Suguru;Iwata So;Aoki Junken;Hosoya Takamitsu;Hagiwara Masatoshi
与正常细胞相比，癌细胞的代谢活动发生了改变，癌症特异性途径成为潜在的治疗靶点。较高的细胞葡萄糖消耗会导致较低的葡萄糖水平，这是癌细胞的一个标志。在低糖条件下诱导细胞死亡的化学物质的客观筛选中，我们发现了一种化合物，称为ALESIA（抗癌配体增强饥饿诱导的细胞凋亡）。通过HEK293A细胞中转化生长因子α的脱落实验，我们确定ALESIA作为鞘氨醇-1-磷酸受体3 - g12偏向的激动剂，促进一氧化氮的产生和氧化应激。ALESIA引发的氧化应激导致葡萄糖耗竭，细胞NADPH缺乏，进而导致癌细胞死亡。腹腔注射ALESIA可提高腹膜弥散性横纹肌肉瘤小鼠的存活率，提示其有可能成为葡萄糖饥饿治疗的新型抗癌药物。
Metabolic activities are altered in cancer cells compared with those in normal cells, and the cancer-specific pathway becomes a potential therapeutic target. Higher cellular glucose consumption, which leads to lower glucose levels, is a hallmark of cancer cells. In an objective screening for chemicals that induce cell death under low-glucose conditions, we discovered a compound, denoted as ALESIA (Anticancer Ligand Enhancing Starvation-induced Apoptosis). By our shedding assay of transforming growth factor α in HEK293A cells, ALESIA was determined to act as a sphingosine-1-phosphate receptor 3–G12-biased agonist that promotes nitric oxide production and oxidative stress. The oxidative stress triggered by ALESIA resulted in the exhaustion of glucose, cellular NADPH deficiency, and then cancer cell death. Intraperitoneal administration of ALESIA improved the survival of mice with peritoneally disseminated rhabdomyosarcoma, indicating its potential as a new type of anticancer drug for glucose starvation therapy.