Studies of the mechanism by which increased spermidine/spermine N1-acetyltransferase activity increases susceptibility to skin carcinogenesis.
Studies of the mechanism by which increased spermidine/spermine N1-acetyltransferase activity increases susceptibility to skin carcinogenesis.
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研究亚精胺/精胺 N1-乙酰转移酶活性增加增加皮肤癌易感性的机制。
DOI：
10.1093/carcin/bgm162
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发表时间：
2007
期刊：
影响因子：
4.7
通讯作者：
Pegg,AnthonyE
中科院分区：
文献类型：
--
作者：
Wang,Xiaojing;Feith,DavidJ;Welsh,Pat;Coleman,CatherineS;Lopez,Christina;Woster,PatrickM;O'Brien,ThomasG;Pegg,AnthonyE
先前的研究表明，角蛋白6（K6）-亚精胺/精胺N1-乙酰转移酶（SSAT）转基因小鼠，适度过度表达SSAT的皮肤，是更敏感的肿瘤诱导的两个阶段的肿瘤发生方案，使用7，12-二甲基苯并[a]蒽（DMBA）启动和促进与12-O-十四烷酰佛波醇-13-乙酸酯（TPA）。为了评估多胺和氧化应激水平的改变在这种增加中的作用，进行了研究与药理学和遗传操作的K6-SSAT小鼠进行DMBA/TPA致癌。增加的肿瘤发生率部分地通过用1，4-双-[N-（丁-2，3-二烯基）氨基]丁烷（防止乙酰化多胺降解的乙酰多胺氧化酶的抑制剂）治疗来防止。这一结果表明，有毒产品，如活性氧和醛类释放的作用，多胺氧化酶对乙酰化的多胺形成的SSAT可能会促进肿瘤的发展。K6-SSAT小鼠与K6-antizyme（AZ）小鼠（表达AZ，一种鸟氨酸脱羧酶（ODC）的负调节因子）的交配阻断了肿瘤的发展。此外，用ODC抑制剂α-二氟甲基鸟氨酸治疗荷瘤K6-SSAT小鼠，导致已建立的肿瘤完全消退。与此相反，治疗与N1，N11-双（乙基）去甲亚精胺，增加SSAT活性的肿瘤没有增强消退。这些结果表明，K6-SSAT小鼠中的肿瘤进展依赖于ODC活性升高和腐胺水平升高，并且可能通过氧化应激进一步增强。他们支持通过抑制ODC活性或多胺摄取而不是通过增加SSAT表达来调节多胺水平的策略，用于皮肤肿瘤发展高风险个体的癌症化学预防。
Previous studies have shown that keratin 6 (K6)–spermidine/spermineN1-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, α-difluoromethylornithine, resulted in the complete regression of established tumors. In contrast, treatment withN1,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.
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