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: Chenxu Shi, Timothy K Cooper, Diane E McCloskey, Adam B Glick, Lisa M Shantz, David J Feith
• Journal: Carcinogenesis (Carcinogenesis) Vol. 33 Issue 7 Pg. 1310-8 (Jul 2012) ISSN: 1460-2180 [Electronic] England
• PMID: 22610166 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• DNA Primers
• Adenosylmethionine Decarboxylase

Topics

• Adenosylmethionine Decarboxylase (metabolism)
• Animals
• Base Sequence
• DNA Primers
• Mice
• Mice, Transgenic
• Skin Neoplasms (enzymology, pathology)