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

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.

Automated summary

Hepatocellular carcinoma (HCC) depends on exogenous arginine due to repression of urea cycle gene expression and unique dependence on cationic amino acid transporter SLC7A1. Arginine deprivation induces an integrated stress response, leading to HCC cell-cycle arrest and quiescence. Inhibiting GCN2 in arginine-deprived HCC cells promotes a senescent phenotype, making these cells vulnerable to senolytic compounds. Combined dietary arginine deprivation, GCN2 inhibition, and senotherapy show potential for HCC treatment.