RRC ID 73127
Author Suzuki S, Venkatesh D, Kanda H, Nakayama A, Hosokawa H, Lee E, Miki T, Stockwell BR, Yokote K, Tanaka T, Prives C.
Title GLS2 Is a Tumor Suppressor and a Regulator of Ferroptosis in Hepatocellular Carcinoma.
Journal Cancer Res
Abstract UNLABELLED: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.
Volume 82(18)
Pages 3209-3222
Published 2022-9-16
DOI 10.1158/0008-5472.CAN-21-3914
PII 707287
PMID 35895807
MeSH Animals Carcinoma, Hepatocellular* / pathology Cell Line, Tumor Ferroptosis* / genetics Glutamates Glutaminase / genetics Glutaminase / metabolism* Glutamine / metabolism Humans Iron Ketoglutaric Acids Lipid Peroxides Liver Neoplasms* / pathology Mice Reactive Oxygen Species
IF 9.727
DNA material CSII-EF-RfA-IRES2-Venus (RDB04389)