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Cancer Res Treat. 2007 Jun;39(2):82-7. doi: 10.4143/crt.2007.39.2.82. Epub 2007 Jun 30.

The chemopreventive effect of retinoids on cellular NF-kappaB activity induced by NMU and NEU in human malignant keratinocytes.

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Department of Clinical Pathology, Bioindustry and Technology Research Institute, Gwangju Health College, Gwangju, Korea.



Retinoids have been shown to be effective in suppressing tumor development when chemical carcinogens such as N-nitroso-N-methylurea (NMU) and N-nitroso-N-ethylurea (NEU) were used to induce mammary tumors in a variety of animal models. However, the molecular mechanisms associated with the retinoid-mediated chemopreventive process, as linked to transcription factor NF-kappaB activation, for chemoprevention have not been elucidated. The purpose of this study was to determine the implications of NF-kappaB activation on the chemopreventive role of retinoids and their effect on cellular NF-kappaB activity that's induced by known alkylating chemical carcinogens such as NMU and NEU in human transfectant squamous cell carcinoma (SCC-13) cells.


The activity of NF-kappaB, as regulated by chemical carcinogens and retinoids, was determined in cultured human SCC-13 keratinocytes that were transfected with the pNF-kappaB-SEAP-NPT plasmid; this permitted the expression of the secretory alkaline phosphatase (SEAP) reporter gene in response to the NF-kappaB activity, and the plasmid contained the neomycin phosphotransferase (NPT) gene, which confers resistance to geneticin. The reporter enzyme activity was measured using a fluorescence detection assay method.


All-trans retinoic acid and 13-cis retinoic acid induced a reduction of NF-kappaB activity up to 64% and 65%, respectively, compared to the control. For the treatment of the human transfectant cells with chemical carcinogens, all-trans retinoic acid (5 mM) and 13-cis retinoic acid (5 mM) downregulated the cellular NF-kappaB activation up to 83% and 85% compared to the NF-kappaB activity that was upregulated by NMU (5microM) and NEU (5microM), respectively.


These results suggest that the chemopreventive effect of retinoids may be mediated by the downregulated activation of NF-kappaB and that retinoids are implicated in the activation of NF-kappaB in human skin cells.


Chemoprevention; Human keratinocytes; NEU; NF-κB; NMU; Retinoids

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