Studies of the mechanism by which increased spermidine/spermine N1-acetyltransferase activity increases susceptibility to skin carcinogenesis

Abstract

Previous studies have shown that keratin 6 (K6)-spermidine/spermine N1-acetyltransferase (SSAT) transgenic mice, which modestly over-express SSAT in the skin, are more sensitive to tumor induction by a two-stage tumorigenesis protocol using initiation with 7,12-dimethylbenz[a]anthracene (DMBA) and promotion with 12-O-tetradecanoylphorbol-13-acetate (TPA). To evaluate the role of altered levels of polyamines and oxidative stress in this increase, studies were carried out with pharmacologic and genetic manipulation of K6-SSAT mice subjected to DMBA/TPA carcinogenesis. The increased tumor incidence was partially prevented by treatment with 1,4-bis-[N-(buta-2,3-dienyl)amino]butane, an inhibitor of acetylpolyamine oxidase which prevented degradation of the acetylated polyamines. This result suggests that toxic products such as reactive oxygen species and aldehydes liberated by the action of polyamine oxidase on the acetylated polyamines formed by SSAT may enhance tumor development. Breeding of the K6-SSAT mice with K6-antizyme (AZ) mice [which express AZ, a negative regulator of ornithine decarboxylase (ODC)] blocked the development of tumors. In addition, treatment of tumor-bearing K6-SSAT mice with the ODC inhibitor, alpha-difluoromethylornithine, resulted in the complete regression of established tumors. In contrast, treatment with N1,N11-bis(ethyl)norspermidine which increased SSAT activity in the tumors did not enhance regression. These results indicate that the tumor progression in K6-SSAT mice is dependent on elevated ODC activity and increased putrescine levels and may be further enhanced by oxidative stress. They support the use of strategies to modulate polyamine levels through the inhibition of ODC activity or polyamine uptake, but not via increased SSAT expression, for cancer chemoprevention in individuals at high risk for skin tumor development.

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

“…Thus, although acetyl-CoA depletion appears to be involved in the former, alternative metabolic disturbances are likely to be responsible for the latter. Similarly, a recent study found that selective SSAT expression in mouse skin increased sensitivity to chemical carcinogens due to elevations in ODC activity and Put levels, both indicative of increased flux with increased liberation of toxic metabolic by-products (59).…”

Suppression of acetylpolyamine oxidase by selected AP-1 members regulates DNp73 abundance: mechanistic insights for overcoming DNp73-mediated resistance to chemotherapeutic drugs

“…37 Conversely, expression of another polyamine catabolic enzyme SSAT under the keratinocyte-specific K6 promoter was shown to promote skin tumors. 38 Interestingly, treatment of these mice with MDL72527 partially counteracted tumor growth, 38 indicating that inhibition of polyamine catabolism can be a potential therapeutic tool to suppress tumor formation. It is noteworthy that enhanced polyamine synthesis has also been shown to promote tumor growth and progression.…”

“…It is noteworthy that enhanced polyamine synthesis has also been shown to promote tumor growth and progression. 38 For example, overexpression of the polyamine biosynthesis enzymes ODC or SAMDC induced malignant transformation. 38,39 All these observations together suggest that disruption of the homeostatic balance of polyamine ratios and not their overall cellular increase could support tumorigenesis.…”

“…38 For example, overexpression of the polyamine biosynthesis enzymes ODC or SAMDC induced malignant transformation. 38,39 All these observations together suggest that disruption of the homeostatic balance of polyamine ratios and not their overall cellular increase could support tumorigenesis. Our current findings that inhibition of PAOX in DNp73-overexpressing cancer cells increases their sensitivity to apoptosis-inducing chemotherapeutic drugs are consistent with these observations.…”

Possible novel roles of poly(rC)-binding protein 1 in SH-SY5Y neurocytes: an analysis using a dynamic Bayesian network

“…In different cells and tissues, the TGF-β signaling pathway plays different roles [21,22] : it stimulates cell division in fibroblasts but inhibits growth in epithelial cells; it also weakens the cell adhesion effect through inducing the tyrosine phosphorylation of β-catenin, Previous data have shown that SAT is predominantly localized to mitochondria [27] . SAT overexpression is correlated with tumorigenesis [28] . The basic structural unit of the nucleosome is an octamer of four core histones, H2A, H2B, H3, and H4, around which a 146-bp fragment of DNA is wrapped [29] .…”