Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA; Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA.
Department of Medicine, Division of Hematology-Oncology, Hospital of the University of Pennsylvania, Philadelphia, PA, USA; Department of Pediatrics, Comprehensive Bone Marrow Failure Center, Division of Hematology, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Cell Metab. 2022 Aug 2;34(8):1151-1167.e7. doi: 10.1016/j.cmet.2022.06.010. Epub 2022 Jul 14.
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.
肝细胞癌 (HCC) 是一种典型的致命恶性肿瘤，表现出遗传异质性和有限的治疗反应。我们在这里证明，HCC 始终抑制尿素循环基因的表达，从而对外源精氨酸表现出营养缺陷性。令人惊讶的是，精氨酸的摄取完全依赖于阳离子氨基酸转运蛋白 SLC7A1，其抑制作用可在体外和体内减缓 HCC 细胞的生长。此外，精氨酸剥夺会引发一种整合应激反应，促进 HCC 细胞周期停滞和静止，这依赖于一般控制非诱导 2 (GCN2) 激酶。在缺乏精氨酸的 HCC 细胞中抑制 GCN2 会促使其呈现衰老表型，从而使这些细胞容易受到衰老细胞裂解化合物的影响。临床前模型证实，联合饮食精氨酸剥夺、GCN2 抑制和衰老治疗可促进 HCC 细胞凋亡和肿瘤消退。这些数据表明，通过靶向 SLC7A1 以及/或联合精氨酸限制、GCN2 抑制和衰老细胞裂解剂治疗人类肝癌的新策略。
