Tucker Jody M, Murphy John T, Kisiel Nicholas, Diegelman Paula, Barbour Karen W, Davis Celestia, Medda Moussumi, Alhonen Leena, Jänne Juhani, Kramer Debora L, Porter Carl W, Berger Franklin G
Department of Biological Sciences, University of South Carolina, Columbia, South Carolina, USA.
Cancer Res. 2005 Jun 15;65(12):5390-8. doi: 10.1158/0008-5472.CAN-05-0229.
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.
细胞内多胺池通过涉及生物合成、分解代谢和转运的过程进行稳态维持。尽管大多数基于多胺的抗癌策略都针对生物合成，但我们最近发现，在亚精胺/精胺N(1)-乙酰基转移酶-1（SSAT）水平激活多胺分解代谢可抑制小鼠前列腺癌模型中的肿瘤生长。在此，我们研究了不同SSAT表达对Apc(Min/+)（MIN）小鼠肠道肿瘤发生的影响。当MIN小鼠与过量产生SSAT的转基因小鼠杂交时，它们在小肠和结肠中分别形成的腺瘤比正常MIN小鼠多3倍和6倍。尽管SSAT产物N(1)-乙酰亚精胺积累，但由于多胺生物合成酶活性的巨大代偿性增加导致代谢通量增强，亚精胺和精胺池仅略有减少。当MIN小鼠与SSAT基因敲除小鼠杂交时，它们在小肠中形成的腺瘤减少了75%，这表明在基础条件下，SSAT对MIN表型有显著贡献。尽管分解代谢能力丧失，但由于生物合成酶活性的代偿性降低导致代谢通量减少，肿瘤中的亚精胺和精胺池未能显著增加。在SSAT转基因和缺陷型MIN小鼠的肿瘤中均观察到Apc基因座的杂合性缺失，这表明杂合性缺失仍然是主要的致癌机制。基于这些数据，我们提出了一个模型，其中SSAT表达改变了多胺途径的通量，从而引发促进肿瘤发生的代谢事件。SSAT缺失可减少肿瘤发生这一发现表明，对该酶的小分子抑制可能代表一种无毒的胃肠道癌症预防和/或治疗策略。
