Elevated ornithine decarboxylase activity promotes skin tumorigenesis by stimulating the recruitment of bulge stem cells but not via toxic polyamine catabolic metabolites

Abstract

Elevated expression of ornithine decarboxylase (ODC), the regulatory enzyme in polyamine biosynthesis, targeted to the epidermis is sufficient to promote skin tumor development following a single subthreshold dose of dimethylbenz(a)anthracene (DMBA). Since skin tumor promotion involves recruitment of hair follicle bulge stem cells harboring genetic lesions, we assessed the effect of increased epidermal ODC on recruitment of bulge stem cells in ODC-ER transgenic mice in which ODC activity is induced de novo in adult skin with 4-hydroxytamoxifen (4OHT). Bromodeoxyuridine-pulse labeling and use of K15.CrePR1;R26R;ODC-ER triple transgenic mice demonstrated that induction of ODC activity is sufficient to recruit bulge stem cells in quiescent skin. Because increased ODC activity not only stimulates proliferation but also increases reactive oxygen species (ROS) generation via subsequent induction of polyamine catabolic oxidases, we used an inhibitor of polyamine catabolic oxidase activity, MDL72527, to investigate whether ROS generation by polyamine catabolic oxidases contributes to skin tumorigenesis in DMBA-initiated ODC-ER transgenic skin. Newborn ODC-ER transgenic mice and their normal littermates were initiated with a single topical dose of DMBA. To assess tumor development originating from dormant bulge stem cells that possess DMBA-initiated mutations, epidermal ODC activity was induced in ODC-ER mice with 4OHT 5 weeks after DMBA initiation followed by MDL72527 treatment. MDL72527 treatment resulted in a shorter tumor latency time, increased tumor burden, increased conversion to carcinomas, and lower tumor levels of p53. Thus, elevated epidermal ODC activity promotes tumorigenesis by stimulating the recruitment of bulge stem cells but not via ROS generation by polyamine catabolic oxidases.

UVA1-Induced Skin Darkening Is Associated with Molecular Changes Even in Highly Pigmented Skin Individuals

“…This corroborates the fact that the minimal erythemal dose is higher than the minimal pigmentary dose in darker phototypes (Sklar et al, 2013). APC downregulated by 1 gene, known to regulate a diversity of biological processes, such as skin development, homeostasis, pigmentation, and disease including cancer (Lim and Nusse, 2013), was also modulated in the three populations, like ornithine decarboxylase 1, the first enzyme in polyamine synthesis, essential in normal growth, differentiation, and invasiveness of keratinocytes during tumorigenesis promotion (Hayes et al, 2014). The upregulation of the gene encoding matrix metalloproteinase 1 was confirmed in European and Indian subjects in agreement with previous data in lightly pigmented skin (Wang et al, 2014).…”

Keratin-6 driven ODC expression to hair follicle keratinocytes enhances stemness and tumorigenesis by negatively regulating Notch

“…Oncogenic mutations or mutational inactivation of tumor suppressor genes in the epidermal keratinocytes are known to drive the pathogenesis of skin cancers. A recent study using ODC-ER transgenic has shown that augmented epidermal ODC activity in the hair follicle bulge stem cells promotes skin chemical carcinogenesis [17]. …”

“…These promoters respectively target gene expression to inter-follicular epidermis and ORS of hair follicles [7, 17]. Chronic UVB-irradiation of these animals showed significant differences in the tumor phenotype, tumor numbers and tumor volume.…”

Polyamines and transglutaminases: biological, clinical, and biotechnological perspectives

“…Some articles of the issue are devoted to this enzyme. First evidence has been obtained that elevated levels of polyamines alone can stimulate the recruitment of epidermal bulge stem cells Hayes et al (2013). This is a significant finding with regard to the stem cell origin of skin cancer.…”