Glutathione peroxidase 2 knockdown suppresses gastric cancer progression and metastasis via regulation of kynurenine metabolism

Author:

Xu Handong,Hu Can,Wang Yi,Shi Yunfu,Yuan Li,Xu Jingli,Zhang Yanqiang,Chen Jiahui,Wei Qin,Qin JiangjiangORCID,Xu Zhiyuan,Cheng XiangdongORCID

Abstract

AbstractGastric cancer (GC) is among the most lethal malignancies due to its poor early diagnosis and high metastasis rate, and new therapeutic targets are urgently needed to develop effective anti-GC drugs. Glutathione peroxidase-2 (GPx2) plays various roles in tumor progression and patient survival. Herein, we found that GPx2 was overexpressed and negatively correlated with poor prognosis by using clinical GC samples for validation. GPx2 knockdown suppressed GC proliferation, invasion, migration and epithelial-mesenchymal transition (EMT) in vitro and in vivo. In addition, proteomic analysis revealed that GPx2 expression regulated kynureninase (KYNU)-mediated metabolism. As one of the key proteins involved in tryptophan catabolism, KYNU can degrade the tryptophan metabolite kynurenine (kyn), which is an endogenous ligand for AhR. Next, we revealed that the activation of the reactive oxygen species (ROS)-mediated KYNU-kyn-AhR signaling pathway caused by GPx2 knockdown was involved in GC progression and metastasis. In conclusion, our results showed that GPx2 acted as an oncogene in GC and that GPx2 knockdown suppressed GC progression and metastasis by suppressing the KYNU-kyn-AhR signaling pathway, which was caused by the accumulation of ROS.

Funder

National Natural Science Foundation of China

Natural Science Foundation of Zhejiang Province

Publisher

Springer Science and Business Media LLC

Subject

Cancer Research,Genetics,Molecular Biology

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