2. Academic Validation
  3. GCN2 inhibition sensitizes arginine-deprived hepatocellular carcinoma cells to senolytic treatment

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

  • Cell Metab. 2022 Aug 2;34(8):1151-1167.e7. doi: 10.1016/j.cmet.2022.06.010.
Rindert Missiaen 1,  Nicole M Anderson 1,  Laura C Kim 1,  Bailey Nance 1,  Michelle Burrows 1,  Nicolas Skuli 1,  Madeleine Carens 1,  Romain Riscal 1,  An Steensels 2,  Fuming Li 1,  M Celeste Simon 3
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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. Electronic address: celeste2@pennmedicine.upenn.edu.
PMID: 35839757 DOI: 10.1016/j.cmet.2022.06.010
Abstract

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.

Keywords

GCN2; arginine; hepatocellular carcinoma; senescence; urea cycle.

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