2022年7月14日，美国宾夕法尼亚大学M. Celeste Simon小组在《细胞—代谢》杂志在线发表论文。该研究发现，抑制GCN2可使缺乏精氨酸的肝癌细胞对衰老治疗敏感。

研究人员发现，肝细胞癌（HCC）持续压制尿素循环基因的表达，从而成为外源性精氨酸的营养缺陷型。令人惊讶的是，精氨酸的摄入是唯一依赖于阳离子氨基酸转运体SLC7A1的，它的抑制减缓了HCC细胞在体外和体内的生长。此外，精氨酸被剥夺会引起一个综合的应激反应，促进HCC细胞周期的停滞和静止，这依赖于general control nonderepressible 2（GCN2）激酶。抑制精氨酸匮乏的HCC细胞中的GCN2反而会促进衰老表型，使这些细胞容易受到衰老化合物的影响。临床前模型证实，联合饮食中的精氨酸剥夺、GCN2抑制和衰老疗法能促进HCC细胞凋亡和肿瘤消退。

这些数据表明，通过靶向SLC7A1和/或结合限制精氨酸、抑制GCN2和衰老剂来治疗人类肝癌的新策略。

据悉，肝细胞癌（HCC）是一种典型的致命的恶性肿瘤，表现出遗传的异质性和有限的治疗反应。

附：英文原文

Title: GCN2 inhibition sensitizes arginine-deprived hepatocellular carcinoma cells to senolytic treatment

Author: Rindert Missiaen, Nicole M. Anderson, Laura C. Kim, Bailey Nance, Michelle Burrows, Nicolas Skuli, Madeleine Carens, Romain Riscal, An Steensels, Fuming Li, M. Celeste Simon

Issue&Volume: 2022-07-14

Abstract: Hepatocellular carcinoma (HCC) is a typically fatal malignancy exhibiting geneticheterogeneity and limited therapy responses. We demonstrate here that HCCs consistentlyrepress urea cycle gene expression and thereby become auxotrophic for exogenous arginine.Surprisingly, arginine import is uniquely dependent on the cationic amino acid transporterSLC7A1, whose inhibition slows HCC cell growth in vitro and in vivo. Moreover, arginine deprivation engages an integrated stress response that promotesHCC cell-cycle arrest and quiescence, dependent on the general control nonderepressible2 (GCN2) kinase. Inhibiting GCN2 in arginine-deprived HCC cells promotes a senescentphenotype instead, rendering these cells vulnerable to senolytic compounds. Preclinicalmodels confirm that combined dietary arginine deprivation, GCN2 inhibition, and senotherapypromote HCC cell apoptosis and tumor regression. These data suggest novel strategiesto treat human liver cancers through targeting SLC7A1 and/or a combination of argininerestriction, inhibition of GCN2, and senolytic agents.

DOI: 10.1016/j.cmet.2022.06.010

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(22)00230-3