Potent modulation of intestinal tumorigenesis in Apcmin/+ mice by the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase.
Potent modulation of intestinal tumorigenesis in Apcmin/+ mice by the polyamine catabolic enzyme spermidine/spermine N1-acetyltransferase.
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DOI：
10.1158/0008-5472.can-05-0229
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发表时间：
2005-06
期刊：
影响因子：
11.2
通讯作者：
J. M. Tucker;J. Murphy;N. Kisiel;P. Diegelman;K. Barbour;Celestia Davis;M. Medda;L. Alhonen;J. Jänne;D. Kramer;C. Porter;F. Berger
中科院分区：
文献类型：
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作者：
J. M. Tucker;J. Murphy;N. Kisiel;P. Diegelman;K. Barbour;Celestia Davis;M. Medda;L. Alhonen;J. Jänne;D. Kramer;C. Porter;F. Berger
细胞内多胺库通过生物合成、催化和运输等过程维持稳态。虽然大多数基于多胺的抗癌策略靶向生物合成，但我们最近发现，在精脒/精胺N（1）-乙酰转移酶-1（SSAT）水平上激活多胺催化剂可抑制小鼠前列腺癌模型中的肿瘤生长。在此，我们研究了差异SSAT表达对Apc（Min/+）（MIN）小鼠肠道肿瘤发生的影响。当MIN小鼠与SSAT过量产生的转基因小鼠杂交时，它们在小肠和结肠中的腺瘤分别比正常MIN小鼠多3倍和6倍。尽管积累的SSAT产品，N（1）-乙酰亚精胺，亚精胺和精胺池仅略有下降，由于一个巨大的补偿性增加，多胺生物合成酶的活动，引起增强代谢通量。当MIN小鼠与SSAT基因敲除小鼠杂交时，它们的小肠腺瘤减少了75%，这表明在基础条件下，SSAT对MIN表型有显着贡献。尽管在分解代谢能力的损失，肿瘤亚精胺和精胺池未能显着增加，由于生物合成酶活性的代偿性降低，引起代谢通量减少。从SSAT转基因和缺陷MIN小鼠的肿瘤中观察到Apc基因座的杂合性丢失，表明杂合性丢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表达改变通过多胺途径的流量，从而引起代谢事件，促进肿瘤发生。SSAT的缺失减少肿瘤发生的发现表明，酶的小分子抑制可能代表胃肠道癌症的无毒预防和/或治疗策略。
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.