The effect of cyclooxygenase-2 overexpression on skin carcinogenesis is context dependent.
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.
Rundhaug
Joyce E
JE
Department of Carcinogenesis, The University of Texas M.D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, USA.
Pavone
Amy
A
Kim
Eunjung
E
Fischer
Susan M
SM
D015127:9,10-Dimethyl-1,2-benzanthracene / Q000633:toxicity; D000818:Animals; D000875:Anthralin / Q000494:pharmacology; D015152:Blotting, Northern; D015153:Blotting, Western; D002273:Carcinogens / Q000633:toxicity; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000502:physiology*; D003879:Dermatologic Agents / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D053582:Interleukin-1alpha / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D009955:Ornithine Decarboxylase / Q000378:metabolism; D012878:Skin Neoplasms / Q000139:chemically induced / Q000201:enzymology* / Q000473:pathology; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D002273:Carcinogens; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D003879:Dermatologic Agents; D053582:Interleukin-1alpha; D014409:Tumor Necrosis Factor-alpha; D015127:9,10-Dimethyl-1,2-benzanthracene; D000242:Cyclic AMP; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2; D009955:Ornithine Decarboxylase; D013755:Tetradecanoylphorbol Acetate; D000875:Anthralin