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.

Polyamines and cancer: implications for chemotherapy and chemoprevention

“…In contrast, Shi et al demonstrated that a targeted overexpression of AdoMetDC in the skin surprisingly resulted in fewer tumours when compared to control littermates (Ref. 71). A recent study suggests a tumour suppressive role for AdoMetDC by demonstrating that the heterozygous deletion of AdoMetDC and the translational protein eIF5A occur concurrently in human lymphoma and mouse lymphomagenesis (Ref.…”

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

“…A variety of transgenic mice with keratin promoter-driven overexpres-sion of key polyamine regulatory proteins have been used in this mouse skin chemical carcinogenesis model. Although TPA induces two rate-limiting enzymes in polyamine biosynthesis, ODC (O’Brien 1976) and AdoMetDC (Scalabrino et al 1980), overexpression of these enzymes targeted to the skin of transgenic mice results in different effects on tumor development (O’Brien et al 1997; Shi et al 2012). Elevated levels of epidermal ODC are sufficient to promote the development of skin tumors following a variety of initiating events including DMBA (O’Brien et al 1997; Chen et al 2000), UV irradiation (Ahmad et al 2001), and oncogenes (Smith et al 1998; Lan et al 2005) without the use of tumor-promoting agents.…”

“…Elevated levels of epidermal ODC are sufficient to promote the development of skin tumors following a variety of initiating events including DMBA (O’Brien et al 1997; Chen et al 2000), UV irradiation (Ahmad et al 2001), and oncogenes (Smith et al 1998; Lan et al 2005) without the use of tumor-promoting agents. In contrast, increased epidermal Ado-MetDC expression is not a sufficient stimulus to drive tumor promotion following DMBA initiation alone (Shi et al 2012). Indeed, increased epidermal AdoMetDC expression suppresses skin tumor promotion in DMBA-initiated/TPA-promoted mice (Shi et al 2012).…”

“…In contrast, increased epidermal Ado-MetDC expression is not a sufficient stimulus to drive tumor promotion following DMBA initiation alone (Shi et al 2012). Indeed, increased epidermal AdoMetDC expression suppresses skin tumor promotion in DMBA-initiated/TPA-promoted mice (Shi et al 2012). Moreover, increased epidermal spermine synthase activity has no effect on skin tumor development in transgenic mice subjected to a DMBA/TPA carcinogenesis protocol (Welsh et al 2012).…”

Attempts at Organ-specific In Vivo Short-term Tests for Environmental Mutagens and Carcinogens in Rodent Liver and Stomach

“…Polyamine content is tightly regulated through biosynthesis, catabolism, uptake, and eOEux mechanisms to maintain optimal levels that are required for cellular events such as DNA replication, gene transcription, mRNA translation and ion channel function. Excess polyamine accumulation is linked to neoplastic growth (82). We assayed ODC activity as a measure of potential tumor promoting activity.…”