CArG-driven GADD45α activated by resveratrol inhibits lung cancer cells
Qiwen Shi1,2, Werner Geldenhuys1, Vijaykumar Sutariya3, Anupam Bishayee4, Isha Patel5 and Deepak Bhatia5
1 Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA
2 School of Biomedical Sciences, Kent State University, Kent, Ohio, USA
3 Department of Pharmaceutical Sciences, University of South Florida, Tampa, Florida, USA
4 Department of Pharmaceutical Sciences, Larkin Health Sciences Institute College of Pharmacy, Miami, Florida, USA
5 Bernard J. Dunn School of Pharmacy, Shenandoah University, Ashburn, Virginia, USA
Correspondence:
Deepak Bhatia, email:
Keywords: resveratrol, CArG elements, Egr-1, GADD45α, gene therapy, synthetic promoters
Received: January 8, 2015 Accepted: April 27, 2015 Published: May 3, 2015
Abstract
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.
