Helping Eve Overcome ADAM: G-Quadruplexes in theADAM-15 Promoter as New Molecular Targets for Breast Cancer Therapeutics

Molecules

Vanessa C. Gaerig¹  Robert V. Brown¹  Tracy A. Brooks²  Taesha Simmons² 

[1] College of Pharmacy, The University of Arizona, Tucson, AZ 85721, USA;Department of Pharmacology, School of Pharmacy, The University of Mississippi, University,MS 38677, USA;

关键词: G-quadruplex;    ADAM-15;    breast cancer;   

DOI  :  10.3390/molecules181215019

来源: DOAJ

【 摘 要 】

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 withinthe 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.

【 授权许可】

Unknown