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Chemical-Induced Skin Carcinogenesis Model Using Dimethylbenz[a]Anthracene and 12-O-Tetradecanoyl Phorbol-13-Acetate (DMBA-TPA)
Published on: December 19, 2019
The effect of PPARgamma ligands on UV- or chemically-induced carcinogenesis in mouse skin
Guobin He1, Stephanie Muga, Philippe Thuillier
1The University of Texas M. D. Anderson Cancer Center, Science Park-Research Division, Smithville, Texas 78957, USA.
Abstract:
Peroxisome proliferator-activated receptor gamma (PPARgamma) is a ligand activated transcription factor. There have been suggestions that PPARgamma ligands may have utility in preventing tumor development in rodent mammary glands and colon. The recent finding that mice lacking one allele of the PPARgamma gene were significantly more susceptible to 7,12-dimethylbenz[a]anthracene (DMBA)-induced skin carcinogenesis compared to wild-type mice highlights mouse skin as another potential organ in which PPARgamma ligands may be effective as chemopreventive agents. In this study, we assessed the effect of two PPARgamma ligands (rosiglitazone and troglitazone) on UV and DMBA/12-O-tetradecanoylphorbol-13-acetate (TPA)-induced mouse skin carcinogenesis, two of the most commonly used mouse skin carcinogenesis models. Unexpectedly, neither rosiglitazone (dietary 200 ppm) nor troglitazone (topical 100 microg) significantly inhibited UV-induced skin tumor development in SKH-1 hairless mice. Likewise, dietary rosiglitazone did not statistically significantly inhibit DMBA/TPA-induced skin tumor development. Interestingly, dietary troglitazone significantly inhibited basal level keratinocyte proliferation as shown by 5-bromo-2'-deoxyuridine (BrdU) labeling, but it had no effect on TPA-induced epidermal cell proliferation. Northern blot analysis showed that PPARgamma expression was extremely low in normal mouse epidermis and was virtually undetectable in skin tumors. Collectively, our data suggest that PPARgamma ligands may not be useful in the prevention of chemically or UV-induced skin tumors.
Insights
PPARgamma ligands, like rosiglitazone and troglitazone, did not prevent skin tumors in mice. These compounds showed no significant effect on UV or chemically induced skin carcinogenesis, suggesting limited chemopreventive potential.
Area of Science:
- Oncology
- Dermatology
- Molecular Biology
Background:
- Peroxisome proliferator-activated receptor gamma (PPARgamma) ligands are investigated for cancer chemoprevention.
- Previous studies suggest PPARgamma's role in preventing mammary and colon tumor development.
- Mice with reduced PPARgamma gene expression show increased susceptibility to skin carcinogenesis.
Purpose of the Study:
- To evaluate the chemopreventive efficacy of PPARgamma ligands (rosiglitazone and troglitazone) against UV and DMBA/TPA-induced skin carcinogenesis in mice.
- To determine the effect of these ligands on keratinocyte proliferation and PPARgamma expression in mouse skin.
Main Methods:
- Utilized SKH-1 hairless mice subjected to UV irradiation or DMBA/TPA treatment.
- Administered rosiglitazone and troglitazone via diet or topical application.
- Assessed tumor development, keratinocyte proliferation (BrdU labeling), and PPARgamma expression (Northern blot analysis).
Main Results:
- Neither rosiglitazone nor troglitazone significantly inhibited UV-induced skin tumor formation.
- Dietary rosiglitazone did not significantly inhibit DMBA/TPA-induced skin tumors.
- Troglitazone reduced basal keratinocyte proliferation but not TPA-induced proliferation; PPARgamma expression was minimal in normal epidermis and skin tumors.
Conclusions:
- PPARgamma ligands (rosiglitazone, troglitazone) demonstrated no significant chemopreventive effect against UV or chemically induced skin tumors in mice.
- The low expression of PPARgamma in mouse skin suggests it may not be a primary target for skin cancer chemoprevention.
- Further research is needed to explore alternative therapeutic strategies for skin cancer prevention.
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