Suppression of natural killer cells by sorafenib contributes to prometastatic effects in hepatocellular carcinoma

PLoS One. 2013;8(2):e55945. doi: 10.1371/journal.pone.0055945. Epub 2013 Feb 8.


Sorafenib, a multi-tyrosine kinase inhibitor, is a standard treatment for advanced hepatocellular carcinoma (HCC). The present study was undertaken to determine whether the growth and metastasis of HCC were influenced in mice receiving sorafenib prior to implantation with tumors, and to investigate the in-vivo and in-vitro effect of sorafenib on natural killer (NK) cells. In sorafenib-pretreated BALB/c nu/nu mice and C57BL/6 mice, tumor growth was accelerated, mouse survival was decreased, and lung metastasis was increased. However, the depletion of NK1.1(+) cells in C57BL/6 mice eliminated sorafenib-mediated pro-metastatic effects. Sorafenib significantly reduced the number of NK cells and inhibited reactivity of NK cells against tumor cells, in both tumor-bearing and tumor-free C57BL/6 mice. Sorafenib down-regulated the stimulatory receptor CD69 in NK cells of tumor-bearing mice, but not in tumor-free mice, and inhibited proliferation of NK92-MI cells, which is associated with the blocking of the PI3K/AKT pathway, and inhibited cytotoxicity of NK cells in response to tumor targets, which was due to impaired ERK phosphorylation. These results suggest immunotherapeutic approaches activating NK cells may enhance the therapeutic efficacy of sorafenib in HCC patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antigens, CD / metabolism
  • Antigens, Differentiation, T-Lymphocyte / metabolism
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / pharmacology*
  • Antineoplastic Agents / toxicity
  • Carcinoma, Hepatocellular / immunology*
  • Carcinoma, Hepatocellular / mortality
  • Carcinoma, Hepatocellular / pathology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Humans
  • Immunocompromised Host
  • Immunosuppressive Agents / administration & dosage
  • Immunosuppressive Agents / pharmacology
  • Immunosuppressive Agents / toxicity
  • K562 Cells
  • Killer Cells, Natural / drug effects*
  • Killer Cells, Natural / immunology
  • Lectins, C-Type / metabolism
  • Liver Neoplasms / immunology*
  • Liver Neoplasms / mortality
  • Liver Neoplasms / pathology*
  • Lung Neoplasms / pathology
  • Lung Neoplasms / secondary
  • MAP Kinase Signaling System / drug effects
  • Male
  • Mice
  • Neoplasm Metastasis
  • Niacinamide / administration & dosage
  • Niacinamide / analogs & derivatives*
  • Niacinamide / pharmacology
  • Phenylurea Compounds / administration & dosage
  • Phenylurea Compounds / pharmacology*
  • Phosphatidylinositol 3-Kinases / metabolism
  • Proto-Oncogene Proteins c-akt / metabolism
  • Proto-Oncogene Proteins c-raf / metabolism
  • Signal Transduction / drug effects
  • Sorafenib
  • Tumor Burden / drug effects
  • Xenograft Model Antitumor Assays


  • Antigens, CD
  • Antigens, Differentiation, T-Lymphocyte
  • Antineoplastic Agents
  • CD69 antigen
  • Immunosuppressive Agents
  • Lectins, C-Type
  • Phenylurea Compounds
  • Niacinamide
  • Sorafenib
  • Phosphatidylinositol 3-Kinases
  • Proto-Oncogene Proteins c-akt
  • Proto-Oncogene Proteins c-raf

Grant support

This work was supported jointly by the National Natural Science Foundation of China (No. 8102010802, 811018715, 81020108025, 81101871, 81101564), the National Key Project for Infectious Diseases (2012ZX10002012-004). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.