Tumor Suppressor Activity of ODC Antizyme in MEK-Driven Skin Tumorigenesis

The study demonstrated that ornithine decarboxylase (ODC) played a crucial role in the development of basal cell carcinomas (BCCs) in Ptch1+/– mice, which are predisposed to these tumors due to mutations in the PTCH gene. Overexpression of ODC in these mice accelerated BCC induction following UVB exposure, while inhibition of ODC through antizyme overexpression or oral administration of the ODC inhibitor α-difluoromethylornithine reduced BCC formation. These findings suggested that targeting ODC could be an effective chemopreventive strategy against BCCs in humans.

The study demonstrated that ornithine decarboxylase (ODC) played a crucial role in the development of basal cell carcinomas (BCCs) in Ptch1+/– mice, which are predisposed to these tumors due to mutations in the patched (PTCH) gene. Overexpression of ODC in these mice accelerated BCC induction following UVB exposure, while inhibition of ODC through antizyme (AZ) overexpression or the use of the ODC inhibitor α-difluoromethylornithine reduced BCC formation. These findings suggested that targeting ODC could be an effective chemopreventive strategy for reducing BCCs in humans.

The study investigated the effects of TPA-stimulated polyamine biosynthesis on metastatic squamous cell carcinoma (mSCC) development in protein kinase C epsilon (PKC epsilon) transgenic mice. It was found that TPA treatment significantly increased epidermal ornithine decarboxylase (ODC) activity and putrescine levels in these mice compared to wild-type littermates. The development of mSCC was completely prevented by administering alpha-difluoromethylornithine (DFMO), an ODC inhibitor, in the drinking water during TPA promotion. However, this treatment resulted in marked hair loss and a decrease in intact hair follicles in the transgenic mice. The findings suggested a link between TPA-induced ODC activity, putrescine accumulation, hair follicle maintenance, and mSCC development, with the observed hair loss being a novel side effect not previously reported in other cancer prevention models.

The study used transgenic mice with targeted expression of spermidine/spermine N1-acetyltransferase (SSAT) in hair follicle keratinocytes to investigate susceptibility to skin cancer. These K6-SSAT transgenic mice, bred onto a tumor-resistant C57BL/6 background, showed a 10-fold increase in epidermal tumors when exposed to a carcinogenesis protocol involving 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate. The transgenic mice exhibited elevated SSAT activity and protein levels, along with increased putrescine and N1-acetylspermidine, indicating enhanced polyamine catabolism. The study concluded that this activation of polyamine catabolism might play a crucial role in chemically induced skin cancer, as evidenced by the early onset and progression to carcinomas in the transgenic mice.

The study demonstrated that elevated levels of ornithine decarboxylase (ODC) and polyamines, when combined with a mutant Ha-ras gene, led to spontaneous tumor development in double transgenic mice. These mice, which were bred to carry both K6/ODC and v-Ha-ras transgenes, developed well-differentiated keratoacanthomas, some of which progressed to carcinomas within 2 months. The tumor development was dependent on ODC, as the use of the ODC inhibitor DFMO prevented tumor formation and caused regression. This indicated that ODC overexpression and activated Ha-ras were sufficient for malignant transformation, providing a model to study epithelial tumor development without chemical carcinogens or tumor promoters.

The study investigated the carcinogenic effects of expressing a mutant H-ras oncogene in different epidermal cell populations of mice. It found that targeting the expression to follicular and interfollicular cells using a truncated keratin 5 gene promoter led to the development of acanthotic areas and carcinoma in situ in newborn mice, and papillomas and keratoacanthomas in adults. These benign tumors frequently progressed to malignancy, unlike those induced by other promoters, and did not require wounding or a tumor promoter for formation. The research concluded that the cell type in which tumor initiation occurs, particularly within the hair follicle, significantly influenced the malignant potential of the tumors.

In this study, researchers investigated whether overexpression of ornithine decarboxylase (ODC) was sufficient for tumor promotion in mouse skin. They used transgenic mice with high ODC expression in epidermal keratinocytes and found that these mice were more sensitive to carcinogen initiation compared to controls. Notably, mice with ODC overexpression in hair follicle keratinocytes developed tumors without the need for additional tumor promoters. The study concluded that ODC overexpression was sufficient to activate target cells in hair follicles, leading to clonal expansion and epidermal tumor formation, indicating that hair follicles are key sites for chemical carcinogen targeting in the skin.