A targetable LIFR−NF-κB−LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis
Copyright policy )A targetable LIFR−NF-κB−LCN2 axis controls liver tumorigenesis and vulnerability to ferroptosis
AbstractThe 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.
- The University of Texas System United States
- Chinese Academy of Sciences China (People's Republic of)
- University of California, San Francisco United States
- University of Chinese Academy of Sciences China (People's Republic of)
- Center for Neuroscience and Regenerative Medicine United States
Male, Leukemia Inhibitory Factor Receptor alpha Subunit, Carcinogenesis, Inbred C57BL, Piperazines, Mice, Non-Receptor Type 6, 2.1 Biological and endogenous factors, Aetiology, Neutralizing, Cancer, Tumor, Liver Disease, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Q, Liver Neoplasms, NF-kappa B, Sorafenib, Up-Regulation, Gene Expression Regulation, Neoplastic, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Biotechnology, Signal Transduction, Liver Cancer, Carcinoma, Hepatocellular, Science, 610, Down-Regulation, Antibodies, Article, Cell Line, Rare Diseases, Lipocalin-2, Cell Line, Tumor, Animals, Ferroptosis, Humans, Neoplastic, Carcinoma, Hepatocellular, Xenograft Model Antitumor Assays, Antibodies, Neutralizing, Mice, Inbred C57BL, Good Health and Well Being, HEK293 Cells, Gene Expression Regulation, Protein Tyrosine Phosphatase, Digestive Diseases
Male, Leukemia Inhibitory Factor Receptor alpha Subunit, Carcinogenesis, Inbred C57BL, Piperazines, Mice, Non-Receptor Type 6, 2.1 Biological and endogenous factors, Aetiology, Neutralizing, Cancer, Tumor, Liver Disease, Protein Tyrosine Phosphatase, Non-Receptor Type 6, Q, Liver Neoplasms, NF-kappa B, Sorafenib, Up-Regulation, Gene Expression Regulation, Neoplastic, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, Biotechnology, Signal Transduction, Liver Cancer, Carcinoma, Hepatocellular, Science, 610, Down-Regulation, Antibodies, Article, Cell Line, Rare Diseases, Lipocalin-2, Cell Line, Tumor, Animals, Ferroptosis, Humans, Neoplastic, Carcinoma, Hepatocellular, Xenograft Model Antitumor Assays, Antibodies, Neutralizing, Mice, Inbred C57BL, Good Health and Well Being, HEK293 Cells, Gene Expression Regulation, Protein Tyrosine Phosphatase, Digestive Diseases
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