Phorbol ester up-regulates aldose reductase expression in A549 cells: a potential role for aldose reductase in cell cycle modulation

Cell Mol Life Sci. 2005 May;62(10):1146-55. doi: 10.1007/s00018-005-5024-4.


Over-expression of aldose reductase (AR) has been observed in many cancer cells. To clarify the role of AR in tumor cells, we investigated the pathways mediating expression of the AR gene induced by 12-O-tetradecanoylphorbol-13-acetate (TPA), a potent tumor promoter. In A549 human lung adenocarcinoma cells, TPA elicited a dose- and time-dependent increase in AR mRNA level with an elevated enzyme activity. The TPA-induced increase in mRNA level and promoter activity of the AR gene was significantly attenuated in the presence of an inhibitor of protein kinase C, tyrosine kinase, or nuclear factor kappaB (NF-kappaB). TPA augmented the NF-kappaB-dependent gene transcription, indicating the involvement of NF-kappaB in this regulation. Accumulation of TPA-treated cells in S phase was almost completely abolished in the presence of ethyl 1-benzyl-3-hydroxy-2(5H)-oxopyrrole-4-carboxylate, an AR inhibitor. Taken together, TPA augmented the promoter activity of the AR gene via the activation of protein kinase and NF-kappaB. The inhibition of AR may assist in the chemotherapy of malignant tumors by suppressing the rapid growth of cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehyde Reductase / antagonists & inhibitors
  • Aldehyde Reductase / genetics*
  • Aldehyde Reductase / physiology
  • Cell Cycle / drug effects*
  • Cell Cycle / physiology
  • Cell Line, Tumor
  • Cycloheximide / pharmacology
  • Dactinomycin / pharmacology
  • Enzyme Inhibitors / pharmacology
  • Gene Expression / drug effects
  • Humans
  • NF-kappa B / metabolism
  • Promoter Regions, Genetic / genetics
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase Inhibitors / pharmacology
  • Protein-Tyrosine Kinases / antagonists & inhibitors
  • Pyrrolidonecarboxylic Acid / analogs & derivatives
  • Pyrrolidonecarboxylic Acid / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Tetradecanoylphorbol Acetate / pharmacology*
  • Up-Regulation / drug effects
  • Up-Regulation / genetics


  • Enzyme Inhibitors
  • NF-kappa B
  • Protein Kinase Inhibitors
  • Dactinomycin
  • ethyl 1-benzyl-3-hydroxy-2(5H)-oxopyrrole-4-carboxylate
  • Cycloheximide
  • Aldehyde Reductase
  • Protein-Tyrosine Kinases
  • Protein Kinase C
  • Tetradecanoylphorbol Acetate
  • Pyrrolidonecarboxylic Acid