Small molecule inhibition of arylamine N-acetyltransferase Type I inhibits proliferation and invasiveness of MDA-MB-231 breast cancer cells
Small molecule inhibition of arylamine N-acetyltransferase Type I inhibits proliferation and invasiveness of MDA-MB-231 breast cancer cells
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DOI：
10.1016/j.bbrc.2010.01.087
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发表时间：
2010-02-26
影响因子：
3.1
通讯作者：
Minchin, Rodney F.
中科院分区：
文献类型：
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作者：
Tiang, Jacky M.;Butcher, Neville J.;Minchin, Rodney F.
芳胺N-乙酰转移酶1是一种II相代谢酶，与某些乳腺癌亚型有关。虽然它与乳腺癌风险有关，因为它在代谢活化和致癌物解毒中的作用，但最近的研究表明，它可能对细胞生长和存活很重要。为了说明NAT 1在乳腺癌中可能的重要性，我们使用了一种新的小分子酶抑制剂（Rhod-o-hp）来研究乳腺癌细胞系MDA-MB-231的生长和侵袭。该抑制剂通过增加细胞周期的G2/M期细胞的百分比而显著降低细胞生长。Rhod-o-hp还降低了MDA-MB-231细胞在软琼脂中生长的能力。使用体外侵袭测定，抑制剂显著降低了细胞的侵袭性。为了测试这种效应是否是由于NAT 1的抑制，使用基于慢病毒的shRNA方法敲除该酶，并且侵袭潜力显著降低。总之，这项研究的结果表明，NAT 1活性可能是重要的乳腺癌的生长和转移。这项研究表明，NAT 1是乳腺癌治疗的一个新靶点。(C)2010年爱思唯尔公司All rights reserved.
Arylamine N-acetyltransferase 1 is a phase II metabolizing enzyme that has been associated With certain breast cancer subtypes. While it has been linked to breast cancer risk because of its role in the metabolic activation and detoxification of carcinogens, recent studies have suggested it may be important in cell growth and survival. To address the possible importance of NAT1 in breast cancer, we have used a novel small molecule inhibitor (Rhod-o-hp) of the enzyme to examine growth and invasion of the breast adenocarcinoma line MDA-MB-231. The inhibitor significantly reduced cell growth by increasing the percent of cells in G2/M phase of the cell cycle. Rhod-o-hp also reduced the ability of the MDA-MB-231 cells to grow in soft agar. Using an in vitro invasion assay, the inhibitor significantly reduced the invasiveness of the cells. To test whether this effect was due to inhibition of NAT1, the enzyme was knocked down using a lentivirus-based shRNA approach and invasion potential was significantly reduced. Taken together, the results of this study demonstrate that NAT1 activity may be important in breast cancer growth and metastasis. The study suggests that NAT1 is a novel target for breast cancer treatment. (C) 2010 Elsevier Inc. All rights reserved.