title: S-adenosylmethionine decarboxylase overexpression inhibits mouse skin tumor promotion.
abstract: Neoplastic growth is associated with increased polyamine biosynthetic activity and content. Tumor promoter treatment induces the rate-limiting enzymes in polyamine biosynthesis, ornithine decarboxylase (ODC), and S-adenosylmethionine decarboxylase (AdoMetDC), and targeted ODC overexpression is sufficient for tumor promotion in initiated mouse skin. We generated a mouse model with doxycycline (Dox)-regulated AdoMetDC expression to determine the impact of this second rate-limiting enzyme on epithelial carcinogenesis. TetO-AdoMetDC (TAMD) transgenic founders were crossed with transgenic mice (K5-tTA) that express the tetracycline-regulated transcriptional activator within basal keratinocytes of the skin. Transgene expression in TAMD/K5-tTA mice was restricted to keratin 5 (K5) target tissues and silenced upon Dox treatment. AdoMetDC activity and its product, decarboxylated AdoMet, both increased approximately 8-fold in the skin. This enabled a redistribution of the polyamines that led to reduced putrescine, increased spermine, and an elevated spermine:spermidine ratio. Given the positive association between polyamine biosynthetic capacity and neoplastic growth, it was somewhat surprising to find that TAMD/K5-tTA mice developed significantly fewer tumors than controls in response to 7,12-dimethylbenz[a]anthracene/12-O-tetradecanoylphorbol-13-acetate chemical carcinogenesis. Importantly, tumor counts in TAMD/K5-tTA mice rebounded to nearly equal the levels in the control group upon Dox-mediated transgene silencing at a late stage of tumor promotion, which indicates that latent viable initiated cells remain in AdoMetDC-expressing skin. These results underscore the complexity of polyamine modulation of tumor development and emphasize the critical role of putrescine in tumor promotion. AdoMetDC-expressing mice will enable more refined spatial and temporal manipulation of polyamine biosynthesis during tumorigenesis and in other models of human disease.
authors.affiliation: Department of Cellular and Molecular Physiology, Pennsylvania State University College of Medicine Hershey, PA 17033, USA.
authors.forename: Chenxu
authors.initials: C
authors.lastname: Shi
authors.forename: Timothy K
authors.initials: TK
authors.lastname: Cooper
authors.forename: Diane E
authors.initials: DE
authors.lastname: McCloskey
authors.forename: Adam B
authors.initials: AB
authors.lastname: Glick
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Shantz
authors.forename: David J
authors.initials: DJ
authors.lastname: Feith
mesh_terms: D012437:Adenosylmethionine Decarboxylase / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D051379:Mice; D008822:Mice, Transgenic; D012878:Skin Neoplasms / Q000201:enzymology* / Q000473:pathology
chemical_list: D017931:DNA Primers; D012437:Adenosylmethionine Decarboxylase