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Helping Eve Overcome ADAM: G-Quadruplexes in the ADAM-15 Promoter as New Molecular Targets for Breast Cancer Therapeutics
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
* Author to whom correspondence should be addressed.
Received: 25 September 2013; in revised form: 25 November 2013 / Accepted: 26 November 2013 / Published: 5 December 2013
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.
Keywords: G-quadruplex; ADAM-15; breast cancer
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MDPI and ACS Style
Brown, R.V.; Gaerig, V.C.; Simmons, T.; Brooks, T.A. Helping Eve Overcome ADAM: G-Quadruplexes in the ADAM-15 Promoter as New Molecular Targets for Breast Cancer Therapeutics. Molecules 2013, 18, 15019-15034.
Brown RV, Gaerig VC, Simmons T, Brooks TA. Helping Eve Overcome ADAM: G-Quadruplexes in the ADAM-15 Promoter as New Molecular Targets for Breast Cancer Therapeutics. Molecules. 2013; 18(12):15019-15034.
Brown, Robert V.; Gaerig, Vanessa C.; Simmons, Taesha; Brooks, Tracy A. 2013. "Helping Eve Overcome ADAM: G-Quadruplexes in the ADAM-15 Promoter as New Molecular Targets for Breast Cancer Therapeutics." Molecules 18, no. 12: 15019-15034.