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帮助夏娃克服 ADAM：ADAM-15 启动子中的 G-四链体作为乳腺癌治疗的新分子靶点。

Helping Eve overcome ADAM: G-quadruplexes in the ADAM-15 promoter as new molecular targets for breast cancer therapeutics.

机构信息

College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA.

出版信息

Molecules. 2013 Dec 5;18(12):15019-34. doi: 10.3390/molecules181215019.

DOI:10.3390/molecules181215019
PMID:24317528
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC6270510/
Abstract

ADAM-15, with known zymogen, secretase, and disintegrin activities, is a catalytically active member of the ADAM family normally expressed in early embryonic development and aberrantly expressed in various cancers, including breast, prostate and lung. ADAM-15 promotes extracellular shedding of E-cadherin, a soluble ligand for the HER2/neu receptor, leading to activation, increased motility, and proliferation. Targeted downregulation of both ADAM-15 and HER2/neu function synergistically kills breast cancer cells, but to date there are no therapeutic options for decreasing ADAM-15 function or expression. In this vein, we have examined a unique string of guanine-rich DNA within the critical core promoter of ADAM-15. This region of DNA consists of seven contiguous runs of three or more consecutive guanines, which, under superhelical stress, can relax from duplex DNA to form an intrastrand secondary G-quadruplex (G4) structure. Using biophysical and biological techniques, we have examined the G4 formation within the entire and various truncated regions of the ADAM-15 promoter, and demonstrate strong intrastrand G4 formation serving to function as a biological silencer element. Characterization of the predominant G4 species formed within the ADAM-15 promoter will allow for specific drug targeting and stabilization, and the further development of novel, targeted therapeutics.

摘要

ADAM-15 具有已知的酶原、内切酶和整联蛋白水解酶活性，是 ADAM 家族中具有催化活性的成员，正常表达于早期胚胎发育中，在各种癌症中异常表达，包括乳腺癌、前列腺癌和肺癌。ADAM-15 促进 E-钙黏蛋白的细胞外脱落，E-钙黏蛋白是 HER2/neu 受体的可溶性配体，导致激活、增加运动性和增殖。靶向下调 ADAM-15 和 HER2/neu 功能协同杀死乳腺癌细胞，但迄今为止，尚无减少 ADAM-15 功能或表达的治疗选择。有鉴于此，我们研究了 ADAM-15 关键核心启动子内独特的富含鸟嘌呤的 DNA 串。该 DNA 区域由七个连续三个或更多连续鸟嘌呤组成的串联组成，在超螺旋压力下，该 DNA 可以从双链 DNA 松弛形成链内二级 G-四链体（G4）结构。我们使用生物物理和生物学技术检查了 ADAM-15 启动子的全长和各种截断区域内的 G4 形成情况，并证明强烈的链内 G4 形成可作为生物沉默元件发挥作用。对 ADAM-15 启动子内形成的主要 G4 物种的特征描述将允许进行特定的药物靶向和稳定，并进一步开发新型靶向治疗方法。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/11ce/6270510/0881d71b2d8e/molecules-18-15019-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/11ce/6270510/7585a0ce1590/molecules-18-15019-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/11ce/6270510/439d3a0ac68a/molecules-18-15019-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/11ce/6270510/fe4b73787b1e/molecules-18-15019-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/11ce/6270510/c7a70c4ef945/molecules-18-15019-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/11ce/6270510/069965170e13/molecules-18-15019-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/11ce/6270510/0881d71b2d8e/molecules-18-15019-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/11ce/6270510/7585a0ce1590/molecules-18-15019-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/11ce/6270510/439d3a0ac68a/molecules-18-15019-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/11ce/6270510/fe4b73787b1e/molecules-18-15019-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/11ce/6270510/c7a70c4ef945/molecules-18-15019-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/11ce/6270510/069965170e13/molecules-18-15019-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/11ce/6270510/0881d71b2d8e/molecules-18-15019-g006.jpg

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