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 hepatocarcinogenic 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 characterized 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 facilitating the conversion of glutamate to α-ketoglutarate (αKG), 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 ferroptosis through αKG-dependent lipid ROS, which in turn might lay the foundation for a novel therapeutic approach.

中文翻译：

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GLS2 是肝细胞癌中的肿瘤抑制因子和铁死亡调节因子


谷氨酰胺合酶 2 (GLS2) 是谷氨酰胺分解的关键调节因子，之前已被证明具有与肿瘤抑制一致的活性。在这里，我们培育了 Gls2 基因敲除 (KO) 小鼠，这些小鼠会发展为晚期 B 细胞淋巴瘤和肝细胞癌 (HCC)。此外，接受肝癌 Stelic 动物模型 (STAM) 方案的 Gls2 KO 小鼠产生比野生型 (WT) 小鼠更大的 HCC 肿瘤。 GLS2 已被证明可以促进铁死亡，这是一种细胞死亡形式，其特征是铁依赖性脂质过氧化物的积累。与此相一致的是，无论是来自 Gls2 KO 小鼠的细胞还是在 GLS2 耗尽的人类癌细胞中，GLS2 缺陷都赋予了对铁死亡的显着抵抗力。从机制上讲，GLS2（而非 GLS1）通过促进谷氨酸转化为 α-酮戊二酸 (αKG) 来增加脂质活性氧 (ROS) 的产生，从而促进铁死亡。 WT GLS2在人肝腺癌异种移植模型中的异位表达显着缩小了肿瘤大小；通过表达 GLS2 的催化失活形式或通过阻断铁死亡可以消除这种效应。此外，对癌症患者数据集的分析支持了 GLS2 介导的铁死亡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，并且其通过调节谷氨酰胺分解促进铁死亡的能力有助于其肿瘤抑制功能。意义：本研究表明，谷氨酰胺分解的关键调节因子 GLS2 可以通过 αKG 依赖性脂质 ROS 促进铁死亡，从而限制体内 HCC，这反过来可能为新型治疗方法奠定基础。