Butcher Neville J, Tetlow Natasha L, Cheung Catherine, Broadhurst Gysell M, Minchin Rodney F
School of Biomedical Sciences, University of Queensland, St. Lucia, Queensland 4072, Australia.
Cancer Res. 2007 Jan 1;67(1):85-92. doi: 10.1158/0008-5472.CAN-06-2635.
Human arylamine N-acetyltransferases (NAT) bioactivate arylamine and heterocyclic amine carcinogens present in red meat and tobacco products. As a result, factors that regulate expression of NATs have the potential to modulate cancer risk in individuals exposed to these classes of carcinogens. Because epidemiologic studies have implicated well-done meat consumption as a risk factor for prostate cancer, we have investigated the effects of androgens on the expression of arylamine N-acetyltransferase type I (NAT1). We show that NAT1 activity is induced by R1881 in androgen receptor (AR)-positive prostate lines 22Rv1 and LNCaP, but not in the AR-negative PC-3, HK-293, or HeLa cells. The effect of R1881 was dose dependent, with an EC(50) for R1881 of 1.6 nmol/L. Androgen up-regulation of NAT1 was prevented by the AR antagonist flutamide. Real-time PCR showed a significant increase in NAT1 mRNA levels for R1881-treated cells (6.60 +/- 0.80) compared with vehicle-treated controls (1.53 +/- 0.17), which was not due to a change in mRNA stability. The increase in NAT1 mRNA was attenuated by concurrent cycloheximide treatment, suggesting that the effect of R1881 may not be by direct transcriptional activation of NAT1. The dominant NAT1 transcript present following androgen treatment was type IIA, indicating transcriptional activation from the major NAT1 promoter P1. A series of luciferase reporter deletions mapped the androgen responsive motifs to a 157-bp region of P1 located 745 bases upstream of the first exon. These results show that human NAT1 is induced by androgens, which may have implications for cancer risk in individuals.
人类芳胺N - 乙酰基转移酶（NAT）可使存在于红肉和烟草制品中的芳胺和杂环胺致癌物发生生物活化。因此，调节NAT表达的因素有可能改变接触这类致癌物个体的癌症风险。由于流行病学研究表明食用熟透的肉类是前列腺癌的一个风险因素，我们研究了雄激素对I型芳胺N - 乙酰基转移酶（NAT1）表达的影响。我们发现，在雄激素受体（AR）阳性的前列腺细胞系22Rv1和LNCaP中，R1881可诱导NAT1活性，但在AR阴性的PC - 3、HK - 293或HeLa细胞中则不能。R1881的作用呈剂量依赖性，其半数有效浓度（EC50）为1.6 nmol/L。AR拮抗剂氟他胺可阻止雄激素对NAT1的上调作用。实时定量PCR显示，与用赋形剂处理的对照细胞（1.53±0.17）相比，经R1881处理的细胞中NAT1 mRNA水平显著升高（6.60±0.80），这并非由于mRNA稳定性的改变。同时用环己酰亚胺处理可减弱NAT1 mRNA的增加，这表明R1881的作用可能不是通过直接转录激活NAT1。雄激素处理后占主导地位的NAT1转录本是IIA型，表明是从主要的NAT1启动子P1进行转录激活。一系列荧光素酶报告基因缺失实验将雄激素反应基序定位到P1的一个157 bp区域，该区域位于第一个外显子上游745个碱基处。这些结果表明，雄激素可诱导人类NAT1，这可能对个体的癌症风险有影响。
