Caffeine inhibits the proliferation of liver cancer cells and activates the MEK/ERK/EGFR signalling pathway

Basic Clin Pharmacol Toxicol. 2008 Jun;102(6):543-51. doi: 10.1111/j.1742-7843.2008.00231.x. Epub 2008 Mar 16.


Caffeine has been reported to prevent hepatocarcinogenesis. We investigated the molecular mechanisms by which caffeine inhibits the growth of hepatocellular carcinoma (HCC) cells. We found that caffeine inhibited the proliferation of HCC cells via cell cycle arrest independent of apoptosis. We revealed a novel signalling axis for caffeine involving activation of the mitogen-activated ERK-regulating kinase (MEK)/extracellular signal-regulated kinase (ERK) pathway that resulted in the downstream up-regulation of epidermal growth factor receptor (EGFR), although the MEK/ERK/EGFR signalling pathway was not involved in the growth inhibitory effect of caffeine. Our data reveal that caffeine could be a promising candidate for the treatment of patients with HCC.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects
  • Caffeine / pharmacology*
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / metabolism
  • Carcinoma, Hepatocellular / pathology
  • Cell Cycle / drug effects
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cell Survival / drug effects
  • DNA, Neoplasm / analysis
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • ErbB Receptors / metabolism*
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Liver Neoplasms / drug therapy*
  • Liver Neoplasms / metabolism
  • Liver Neoplasms / pathology
  • MAP Kinase Kinase Kinases / metabolism
  • MAP Kinase Signaling System / drug effects*
  • MAP Kinase Signaling System / physiology


  • Antineoplastic Agents
  • DNA, Neoplasm
  • Caffeine
  • ErbB Receptors
  • Extracellular Signal-Regulated MAP Kinases
  • MAP Kinase Kinase Kinases