title: Activated polyamine catabolism depletes acetyl-CoA pools and suppresses prostate tumor growth in TRAMP mice.
abstract: The enzyme spermidine/spermine N(1)-acetyltransferase (SSAT) regulates the catabolism and export of intracellular polyamines. We have previously shown that activation of polyamine catabolism by conditional overexpression of SSAT has antiproliferative consequences in LNCaP prostate carcinoma cells. Growth inhibition was causally linked to high metabolic flux arising from a compensatory increase in polyamine biosynthesis. Here we examined the in vivo consequences of SSAT overexpression in a mouse model genetically predisposed to develop prostate cancer. TRAMP (transgenic adenocarcinoma of mouse prostate) female C57BL/6 mice carrying the SV40 early genes (T/t antigens) under an androgen-driven probasin promoter were cross-bred with male C57BL/6 transgenic mice that systemically overexpress SSAT. At 30 weeks of age, the average genitourinary tract weights of TRAMP mice were approximately 4 times greater than those of TRAMP/SSAT bigenic mice, and by 36 weeks, they were approximately 12 times greater indicating sustained suppression of tumor outgrowth. Tumor progression was also affected as indicated by a reduction in the prostate histopathological scores. By immunohistochemistry, SV40 large T antigen expression in the prostate epithelium was the same in TRAMP and TRAMP/SSAT mice. Consistent with the 18-fold increase in SSAT activity in the TRAMP/SSAT bigenic mice, prostatic N(1)-acetylspermidine and putrescine pools were remarkably increased relative to TRAMP mice, while spermidine and spermine pools were minimally decreased due to a compensatory 5-7-fold increase in biosynthetic enzymes activities. The latter led to heightened metabolic flux through the polyamine pathway and an associated approximately 70% reduction in the SSAT cofactor acetyl-CoA and a approximately 40% reduction in the polyamine aminopropyl donor S-adenosylmethionine in TRAMP/SSAT compared with TRAMP prostatic tissue. In addition to elucidating the antiproliferative and metabolic consequences of SSAT overexpression in a prostate cancer model, these findings provide genetic support for the discovery and development of specific small molecule inducers of SSAT as a novel therapeutic strategy targeting prostate cancer.
authors.affiliation: Department of Pharmacology and Therapeutics, Roswell Park Cancer Institute, Buffalo, New York 14263, USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Kee
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Foster
authors.forename: Salim
authors.initials: S
authors.lastname: Merali
authors.forename: Debora L
authors.initials: DL
authors.lastname: Kramer
authors.forename: Mary L
authors.initials: ML
authors.lastname: Hensen
authors.forename: Paula
authors.initials: P
authors.lastname: Diegelman
authors.forename: Nicholas
authors.initials: N
authors.lastname: Kisiel
authors.forename: Slavoljub
authors.initials: S
authors.lastname: Vujcic
authors.forename: Richard V
authors.initials: RV
authors.lastname: Mazurchuk
authors.forename: Carl W
authors.initials: CW
authors.lastname: Porter
mesh_terms: D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000123:Acetyltransferases / Q000235:genetics* / Q000378:metabolism; D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D000727:Androgen-Binding Protein / Q000235:genetics; D000818:Animals; D000952:Antigens, Polyomavirus Transforming / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D020022:Genetic Predisposition to Disease; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011073:Polyamines / Q000378:metabolism*; D011467:Prostate / Q000473:pathology / Q000503:physiopathology; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D000099228:Diamine N-Acetyltransferase
chemical_list: D000105:Acetyl Coenzyme A; D000123:Acetyltransferases; D000727:Androgen-Binding Protein; D000952:Antigens, Polyomavirus Transforming; D011073:Polyamines; D000099228:Diamine N-Acetyltransferase; C027519:probasin