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Genes Cancer. 2015 May;6(5-6):220-30.

CArG-driven GADD45α activated by resveratrol inhibits lung cancer cells.

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Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA ; School of Biomedical Sciences, Kent State University, Kent, Ohio, USA.
Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA.
Department of Pharmaceutical Sciences, University of South Florida, Tampa, Florida, USA.
Department of Pharmaceutical Sciences, Larkin Health Sciences Institute College of Pharmacy, Miami, Florida, USA.
Bernard J. Dunn School of Pharmacy, Shenandoah University, Ashburn, Virginia, USA.


We report anticarcinogenic effects of suicide gene therapy that relies on the use of resveratrol-responsive CArG elements from the Egr-1 promoter to induce GADD45α. In A549 lung cancer cells, endogenous GADD45α was not induced upon resveratrol treatment. Therefore, induction of exogenous GADD45α resulted in growth inhibition. Resveratrol transiently induced Egr-1 through ERK/JNK-ElK-1. Hence, we cloned natural or synthetic Egr-1 promoter upstream of GADD45α cDNA to create a suicide gene therapy vector. Since natural promoter may have antagonized effects, we tested synthetic promoter that contains either five, six or nine repeats of CArG elements essential in the Egr-1 promoter to drive the expression of GADD45α upon resveratrol treatment. Further analysis confirmed that both synthetic promoter and natural Egr-1 promoter were able to "turn on" the expression of GADD45α when combined with resveratrol, and subsequently led to suppression of cell proliferation and apoptosis.


CArG elements; Egr-1; GADD45a; gene therapy; resveratrol; synthetic promoters

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