GCN2 inhibition sensitizes arginine-deprived hepatocellular carcinoma cells to senolytic treatment.
GCN2 inhibition sensitizes arginine-deprived hepatocellular carcinoma cells to senolytic treatment.
复制标题
GCN 2抑制使缺乏精氨酸的肝细胞癌细胞对衰老清除治疗敏感。
DOI：
10.1016/j.cmet.2022.06.010
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发表时间：
2022-08-02
期刊：
影响因子：
29
通讯作者：
Simon, M. Celeste
中科院分区：
文献类型：
--
作者：
Missiaen, Rindert;Anderson, Nicole M.;Kim, Laura C.;Nance, Bailey;Burrows, Michelle;Skuli, Nicolas;Carens, Madeleine;Riscal, Romain;Steensels, An;Li, Fuming;Simon, M. Celeste
肝细胞癌（HCC）是一种典型的致命性恶性肿瘤，具有遗传异质性和有限的治疗效果。我们在这里证明，hcc持续抑制尿素循环基因表达，从而成为外源精氨酸的营养不良。令人惊讶的是，精氨酸的进口仅依赖于阳离子氨基酸转运体SLC7A1，其抑制作用在体外和体内减缓了HCC细胞的生长。此外，精氨酸剥夺参与综合应激反应，促进HCC细胞周期阻滞和静止，依赖于一般控制非抑制2 （GCN2）激酶。在精氨酸缺失的HCC细胞中抑制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，膳食精氨酸剥夺、GCN2抑制和衰老联合治疗可促进HCC细胞凋亡和肿瘤消退。这些数据提示了通过靶向SLC7A1和/或结合精氨酸限制、抑制GCN2和抗衰老药物治疗人类肝癌的新策略。尿素循环缺陷型肝细胞癌联合精氨酸剥夺、GCN2抑制和抗衰老治疗可抑制肿瘤生长。
Hepatocellular carcinoma (HCC) is a typically fatal malignancy exhibiting genetic heterogeneity and limited therapy responses. We demonstrate here that HCCs consistently repress urea cycle gene expression and thereby become auxotrophic for exogenous arginine. Surprisingly, arginine import is uniquely dependent on the cationic amino acid transporter SLC7A1, whose inhibition slows HCC cell growth in vitro and in vivo. Moreover, arginine deprivation engages an integrated stress response that promotes HCC cell cycle arrest and quiescence, dependent on the General Control Nonderepressible 2 (GCN2) kinase. Inhibiting GCN2 in arginine deprived HCC cells promotes a senescent phenotype instead, rendering these cells vulnerable to senolytic compounds. Preclinical models confirm that combined dietary arginine deprivation, GCN2 inhibition, and senotherapy promote HCC cell apoptosis and tumor regression. These data suggest novel strategies to treat human liver cancers through targeting SLC7A1 and/or a combination of arginine restriction, inhibition of GCN2, and senolytic agents. Combined treatment of urea cycle deficient hepatocellular carcinomas with arginine deprivation, GCN2 inhibition, and senolytic therapy suppresses tumor growth.
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影响因子：
11.2
作者：
Du Q;Zhang X;Liu Q;Zhang X;Bartels CE;Geller DA
通讯作者：
Geller DA
影响因子：
4.6
作者：
Averous J;Lambert-Langlais S;Mesclon F;Carraro V;Parry L;Jousse C;Bruhat A;Maurin AC;Pierre P;Proud CG;Fafournoux P
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Fafournoux P
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4.2
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Rotmann, A
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4
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Ciani, E;Severi, S;Contestabile, A
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Contestabile, A
影响因子：
24.8
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Halaby, Marie Jo;Hezaveh, Kebria;McGaha, Tracy L.
通讯作者：
McGaha, Tracy L.