Activated Polyamine Catabolism Depletes Acetyl-CoA Pools and Suppresses Prostate Tumor Growth in TRAMP Mice

July 2004 in “ Journal of Biological Chemistry ”

Kristin Kee, Barbara A. Foster, Salim Merali, Debora L. Kramer, Mary L. Hensen, Paula Diegelman, Nicholas Kisiel, Slavoljub Vujcic, Richard Mazurchuk, Carl W. Porter

The study explored the impact of overexpressing the enzyme spermidine/spermine N1-acetyltransferase (SSAT) in TRAMP mice, a model for prostate cancer. By cross-breeding these mice with SSAT-overexpressing mice, researchers observed a significant reduction in tumor growth, with genitourinary tract weights being 4 to 12 times less than in TRAMP mice alone by 30 to 36 weeks of age. This tumor suppression was attributed to increased polyamine catabolism, which depleted acetyl-CoA and S-adenosylmethionine, despite increased polyamine biosynthesis. Histopathological analysis showed less advanced tumors in TRAMP/SSAT mice, suggesting that SSAT overexpression could be a promising therapeutic strategy for prostate cancer. Additionally, a genitourinary disease index was developed to assess the treatment's impact, particularly in the C57BL/6 mouse background.

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research Targeted Expression of Spermidine/Spermine N1-Acetyltransferase Increases Susceptibility to Chemically Induced Skin Carcinogenesis

54 citations, February 2002 in “Carcinogenesis”

The study used transgenic mice with targeted expression of spermidine/spermine N1-acetyltransferase (SSAT) in hair follicle keratinocytes to investigate susceptibility to skin cancer. These K6-SSAT transgenic mice, bred onto a tumor-resistant C57BL/6 background, showed a 10-fold increase in epidermal tumors when exposed to a carcinogenesis protocol involving 7,12-dimethylbenz[a]anthracene and 12-O-tetradecanoylphorbol-13-acetate. The transgenic mice exhibited elevated SSAT activity and protein levels, along with increased putrescine and N1-acetylspermidine, indicating enhanced polyamine catabolism. The study concluded that this activation of polyamine catabolism might play a crucial role in chemically induced skin cancer, as evidenced by the early onset and progression to carcinomas in the transgenic mice.

research Relation of Skin Polyamines to the Hairless Phenotype in Transgenic Mice Overexpressing Spermidine/Spermine N1-Acetyltransferase

54 citations, May 2001 in “Journal of Investigative Dermatology”

research Activation of Polyamine Catabolism Profoundly Alters Tissue Polyamine Pools and Affects Hair Growth and Female Fertility in Transgenic Mice Overexpressing Spermidine/Spermine N1-Acetyltransferase

124 citations, July 1997 in “Journal of Biological Chemistry”

In this study, researchers created a transgenic mouse line that overexpressed spermidine/spermine N^1-acetyltransferase, leading to significant alterations in tissue polyamine pools. These changes included the presence of N^1-acetylspermidine, an unusual accumulation of putrescine, and reduced levels of spermidine and spermine. The most notable phenotypic effect was permanent hair loss in mice aged 3 to 4 weeks, associated with the formation of follicular cysts in the dermis, likely due to putrescine's interference with hair follicle cell differentiation and proliferation. Additionally, female mice were infertile, linked to ovarian hypofunction and underdeveloped uteri. This research highlighted the potential of using spermidine/spermine N^1-acetyltransferase overexpression to manipulate polyamine levels in transgenic animals for studying developmental and cancer-related outcomes.