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

• Published in: Amino acids 2014-03, Vol.46 (3), p.543-552
• Main Authors: Hayes, Candace S, DeFeo-Mattox, Karen, Woster, Patrick M, Gilmour, Susan K
• Format: Article
• Language: English
• Subjects: 9,10-Dimethyl-1,2-benzanthracene - administration & dosage; adults; Analytical Chemistry; Animals; anthracenes; Biochemical Engineering; Biochemistry; Biomedical and Life Sciences; biosynthesis; carcinogenesis; carcinoma; Dose-Response Relationship, Drug; Elevated; Enzyme Activation - drug effects; Hair Follicle - metabolism; Hair Follicle - pathology; hair follicles; Life Sciences; metabolites; Mice; Mice, Transgenic; mutation; neonates; Neurobiology; Original Article; ornithine decarboxylase; Ornithine Decarboxylase - metabolism; Ornithine Decarboxylase Inhibitors; Oxidase; Polyamines; Polyamines - metabolism; Proteomics; Putrescine - analogs & derivatives; Putrescine - pharmacology; reactive oxygen species; Reactive Oxygen Species - metabolism; Recruitment; skin neoplasms; Skin Neoplasms - chemically induced; Skin Neoplasms - diagnosis; Skin Neoplasms - metabolism; Stem cells; Structure-Activity Relationship; toxicity; Transgenic; transgenic animals; transgenics; Tumors
• ISSN: 0939-4451; 1438-2199
• DOI: 10.1007/s00726-013-1559-0

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.