The effect of cyclooxygenase-2 overexpression on skin carcinogenesis is context dependent

Mol Carcinog. 2007 Dec;46(12):981-92. doi: 10.1002/mc.20340.


The up-regulation of the inducible form of cyclooxygenase (COX-2), a central enzyme in the prostaglandin (PG) biosynthetic pathway, occurs in many epithelial tumors and has been associated with tumor cell proliferation and angiogenesis. To better understand the role of COX-2 in skin tumor development, we generated transgenic mice that overexpress COX-2 under the control of the keratin 14 promoter. We previously reported (Cancer Res. 62: 2516, 2002) that these mice, referred to as keratin 14 (K14).COX2 mice, were unexpectedly very resistant to 12-O-tetradecanoylphorbol 13-acetate (TPA) tumor promotion. The current studies were undertaken to determine the mechanism of this resistance and determine if it was restricted to TPA promotion. Transgenic and wild-type mice were subjected to a complete carcinogenesis protocol using 7,12-dimethylbenz[a]anthracene (DMBA) only, as well as a two-stage protocol using DMBA plus an unrelated tumor promoter, anthralin. In addition, the responses of transgenic and wild-type mice to TPA in terms of induction of proliferation and various down-stream mediators were examined. The TPA resistance phenotype correlated with a reduced ability to induce ornithine decarboxylase, interleukin-1alpha, and tumor necrosis factor-alpha and a reduced proliferation response. This resistance phenotype appears to be restricted to phorbol ester promotion because K14.COX2 mice developed six times more tumors than wild-type mice when anthralin was used as the tumor promoter. Additionally, K14.COX2 mice treated only with DMBA developed approximately 3.5 times more tumors than wild-type mice, suggesting that PGs have intrinsic tumor promoting activity. We conclude that the role of PGs in skin tumorigenesis is context dependent.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • 9,10-Dimethyl-1,2-benzanthracene / toxicity
  • Animals
  • Anthralin / pharmacology
  • Blotting, Northern
  • Blotting, Western
  • Carcinogens / toxicity
  • Cell Proliferation / drug effects
  • Cell Transformation, Neoplastic / drug effects
  • Cyclic AMP / metabolism
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • Cyclooxygenase 2 / physiology*
  • Dermatologic Agents / pharmacology
  • Drug Resistance, Neoplasm
  • Female
  • Humans
  • Interleukin-1alpha / metabolism
  • Mice
  • Mice, Transgenic
  • Ornithine Decarboxylase / metabolism
  • Skin Neoplasms / chemically induced
  • Skin Neoplasms / enzymology*
  • Skin Neoplasms / pathology
  • Tetradecanoylphorbol Acetate / toxicity
  • Tumor Necrosis Factor-alpha / metabolism


  • Carcinogens
  • Creb1 protein, mouse
  • Cyclic AMP Response Element-Binding Protein
  • Dermatologic Agents
  • Interleukin-1alpha
  • Tumor Necrosis Factor-alpha
  • 9,10-Dimethyl-1,2-benzanthracene
  • Cyclic AMP
  • Ptgs2 protein, mouse
  • Cyclooxygenase 2
  • Ornithine Decarboxylase
  • Tetradecanoylphorbol Acetate
  • Anthralin