Potent Modulation of Intestinal Tumorigenesis in Apcmin/+ Mice by the Polyamine Catabolic Enzyme Spermidine/Spermine N1-acetyltransferase

Abstract

Intracellular polyamine pools are homeostatically maintained by processes involving biosynthesis, catabolism, and transport. Although most polyamine-based anticancer strategies target biosynthesis, we recently showed that activation of polyamine catabolism at the level of spermidine/spermine N 1 -acetyltransferase-1 (SSAT) suppresses tumor outgrowth in a mouse prostate cancer model. Herein, we examined the effects of differential SSAT expression on intestinal tumorigenesis in the Apc Min/+ (MIN) mouse. When MIN mice were crossed with SSAT-overproducing transgenic mice, they developed 3-and 6-fold more adenomas in the small intestine and colon, respectively, than normal MIN mice. Despite accumulation of the SSAT product, N 1 -acetylspermidine, spermidine and spermine pools were only slightly decreased due to a huge compensatory increase in polyamine biosynthetic enzyme activities that gave rise to enhanced metabolic flux. When MIN mice were crossed with SSAT knock-out mice, they developed 75% fewer adenomas in the small intestine, suggesting that under basal conditions, SSAT contributes significantly to the MIN phenotype. Despite the loss in catabolic capability, tumor spermidine and spermine pools failed to increase significantly due to a compensatory decrease in biosynthetic enzyme activity giving rise to a reduced metabolic flux. Loss of heterozygosity at the Apc locus was observed in tumors from both SSAT-transgenic and -deficient MIN mice, indicating that loss of heterozygosity remained the predominant oncogenic mechanism. Based on these data, we propose a model in which SSAT expression alters flux through the polyamine pathway giving rise to metabolic events that promote tumorigenesis. The finding that deletion of SSAT reduces tumorigenesis suggests that small-molecule inhibition of the enzyme may represent a nontoxic prevention and/or treatment strategy for gastrointestinal cancers. (Cancer Res 2005; 65(12): 5390-8)

Polyamine Acetylation Modulates Polyamine Metabolic Flux, a Prelude to Broader Metabolic Consequences

“…Similar biochemical findings to those seen in LNCaP cells were made in transgenic overexpression of SSAT, which led to a hairless phenotype (26) and altered tumor growth (27,28). We now believe that the various effects seen in cells and mice may be due to altered metabolic flux through the polyamine pathway (23).…”

“…Alternatively, it can lead to overproduction of toxic pathway by-products, such as 5Ј-methylthioadenosine, hydrogen peroxide, and aldehydes. These various possibilities have been recently identified as "enhanced flux" by Kee et al (23,27), as a "metabolic ratchet" by Tucker et al (28), and as a "paddlewheel" by Jänne et al (55).…”

“…1). The adverse downstream consequences of sustained metabolic flux that account for growth inhibition and other effects are potentially 2-fold: pathway precursor depletion or accumulation of toxic pathway by-products (23,(27)(28)(29)(30). Examples of the former could include depletion of the SAMDC substrate and methylation precursor, S-adenosylmethionine, or depletion of the SSAT substrate and fatty acid precursor, acetyl-CoA (23,27,30).…”

Polyamines and nonmelanoma skin cancer

“…Indeed, ODC activity and spermidine levels are higher in nontransgenic littermates following tumor promoter treatment and in subsequent skin tumors compared to that seen in UKU 165b transgenic mice (Pietila et al, 2001). It has been hypothesized that the changes in tumor development may arise from a greatly accelerated polyamine metabolic flux which is driven by decreased spermidine and spermine pools that in turn trigger a sustained increase in polyamine biosynthetic activity and a sustained release of reactive by-products (Tucker et al, 2005;Janne et al, 2006). Further studies are obviously needed to better understand the role of SSAT in skin carcinogenesis.…”

Animal disease models generated by genetic engineering of polyamine metabolism

“…When MIN mice, which are greatly predisposed to the development of multiple adenomas in the gastrointestinal tract due to a truncation mutation in adenomatous polyposis coli (Apc) tumor suppressor gene [39,40], were crossed with SSAT overexpressing transgenic mice [34], the hybrid mice developed up to 6 times more intestinal adenomas than the original MIN mice [41]. The view that SSAT expression significantly contributes to the MIN phenotype was strongly strengthened by findings indicating that similar crossing of the MIN mice with SSAT knockout mice reduced the incidence of intestinal adenomas by 75% in comparison with the original MIN mice [41]. The unexpected promotion of intestinal tumorigenesis by SSAT overexpression could possibly be attributed to the enhanced polyamine flux due to compensatory increases in ODC and AdoMet decarboxylase activ-ities and the enhanced generation of potentially harmful by-products, such as hydrogen peroxide and reactive aldehydes, by the SSAT/PAO system.…”