A targetable LIFR-NF-κB-LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis

Nat Commun. 2021 Dec 17;12(1):7333. doi: 10.1038/s41467-021-27452-9.

Abstract

The growing knowledge of ferroptosis has suggested the role and therapeutic potential of ferroptosis in cancer, but has not been translated into effective therapy. Liver cancer, primarily hepatocellular carcinoma (HCC), is highly lethal with limited treatment options. LIFR is frequently downregulated in HCC. Here, by studying hepatocyte-specific and inducible Lifr-knockout mice, we show that loss of Lifr promotes liver tumorigenesis and confers resistance to drug-induced ferroptosis. Mechanistically, loss of LIFR activates NF-κB signaling through SHP1, leading to upregulation of the iron-sequestering cytokine LCN2, which depletes iron and renders insensitivity to ferroptosis inducers. Notably, an LCN2-neutralizing antibody enhances the ferroptosis-inducing and anticancer effects of sorafenib on HCC patient-derived xenograft tumors with low LIFR expression and high LCN2 expression. Thus, anti-LCN2 therapy is a promising way to improve liver cancer treatment by targeting ferroptosis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Neutralizing / pharmacology
  • Carcinogenesis / genetics
  • Carcinogenesis / metabolism*
  • Carcinogenesis / pathology*
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / pathology
  • Carcinoma, Hepatocellular / ultrastructure
  • Cell Line, Tumor
  • Down-Regulation / genetics
  • Ferroptosis*
  • Gene Expression Regulation, Neoplastic
  • HEK293 Cells
  • Humans
  • Leukemia Inhibitory Factor Receptor alpha Subunit / metabolism*
  • Lipocalin-2 / genetics
  • Lipocalin-2 / metabolism*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / metabolism*
  • Liver Neoplasms / pathology*
  • Liver Neoplasms / ultrastructure
  • Male
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism*
  • Piperazines / pharmacology
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6 / metabolism
  • Signal Transduction / drug effects
  • Sorafenib / pharmacology
  • Up-Regulation / drug effects
  • Up-Regulation / genetics
  • Xenograft Model Antitumor Assays

Substances

  • Antibodies, Neutralizing
  • LCN2 protein, human
  • LIFR protein, human
  • Leukemia Inhibitory Factor Receptor alpha Subunit
  • Lipocalin-2
  • NF-kappa B
  • Piperazines
  • erastin
  • Sorafenib
  • PTPN6 protein, human
  • Protein Tyrosine Phosphatase, Non-Receptor Type 6