GLS2 Is a Tumor Suppressor and a Regulator of Ferroptosis in Hepatocellular Carcinoma
GLS2 Is a Tumor Suppressor and a Regulator of Ferroptosis in Hepatocellular Carcinoma
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DOI：
10.1158/0008-5472.can-21-3914
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发表时间：
2022-09-15
期刊：
影响因子：
11.2
通讯作者：
Prives, Carol
中科院分区：
文献类型：
--
作者：
Suzuki, Sawako;Venkatesh, Divya;Prives, Carol
谷氨酰胺合成酶2(GLS2)是谷氨酰胺分解的关键调节因子，与肿瘤抑制相关。在这里，我们产生了Gls2基因敲除(KO)小鼠，这些小鼠发展为迟发性B细胞淋巴瘤和肝细胞癌(HCC)。此外，接受HEPA致癌Stelic动物模型(STAM)方案的Gls2 KO小鼠产生的肝癌肿瘤比野生型(WT)小鼠更大。GLS2已被证明可以促进铁性下垂，这是一种细胞死亡的形式，其特征是铁依赖的过氧化脂质的积累。与此一致的是，GLS2缺乏，无论是来自Gls2KO小鼠的细胞，还是缺失GLS2的人类癌细胞，都赋予了对铁下垂的显著抵抗力。机制上，GLS2，而不是GLS1，通过促进谷氨酸转化为α-酮戊二酸(AKG)而增加脂质活性氧自由基(ROS)的产生，从而促进铁下垂。在人肝腺癌异种移植模型中异位表达WT GLS2显著减小了肿瘤大小；这种作用可以通过表达催化失活形式的GLS2或通过阻断铁下垂而被抵消。此外，对癌症患者数据集的分析支持GLS2介导的铁下垂调节在人类肿瘤抑制中的作用。这些数据表明，GLS2是一种真正的肿瘤抑制因子，其通过调节谷氨酰胺分解来促进铁下垂的能力有助于其肿瘤抑制功能。意义：本研究证明谷氨酰胺分解的关键调节因子GLS2可以通过AKG依赖的脂质ROS促进体内铁代谢来抑制肝癌的发生，这反过来可能为新的治疗方法奠定基础。
Glutamine synthase 2 (GLS2) is a key regulator of glutaminolysis and has been previously implicated in activities consistent with tumor suppression. Here we generated Gls2 knockout (KO) mice that develop late-occurring B-cell lymphomas and hepatocellular carcinomas (HCC). Further, Gls2 KO mice subjected to the hepa-tocarcinogenic Stelic Animal Model (STAM) protocol produce larger HCC tumors than seen in wild-type (WT) mice. GLS2 has been shown to promote ferroptosis, a form of cell death charac-terized by iron-dependent accumulation of lipid peroxides. In line with this, GLS2 deficiency, either in cells derived from Gls2 KO mice or in human cancer cells depleted of GLS2, conferred significant resistance to ferroptosis. Mechanistically, GLS2, but not GLS1, increased lipid reactive oxygen species (ROS) production by facil-itating the conversion of glutamate to a-ketoglutarate (aKG), thereby promoting ferroptosis. Ectopic expression of WT GLS2 in a human hepatic adenocarcinoma xenograft model significantly reduced tumor size; this effect was nullified by either expressing a catalytically inactive form of GLS2 or by blocking ferroptosis. Furthermore, analysis of cancer patient datasets supported a role for GLS2-mediated regulation of ferroptosis in human tumor suppression. These data suggest that GLS2 is a bona fide tumor suppressor and that its ability to favor ferroptosis by regulating glutaminolysis contributes to its tumor suppressive function.Significance: This study demonstrates that the key regulator of glutaminolysis, GLS2, can limit HCC in vivo by promoting ferrop-tosis through aKG-dependent lipid ROS, which in turn might lay the foundation for a novel therapeutic approach.