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Agonists but Decrease HCT-116 Colon Cancer Cell Survival through Receptor-Independent Activation of Early Growth Response-1 and Nonsteroidal Anti-Inflammatory Drug-Activated Gene-1
Department of Biochemistry and Biophysics, College of Agriculture and Life Sciences, Texas A&M University, College Station, Texas (S.C.); Department of Veterinary Physiology and Pharmacology, College of Veterinary Medicine, Texas A&M University, College Station, Texas (S.P., S.S.); Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, Tennessee (S.J.B.); and Institute of Biosciences and Technology, Texas A&M University System Health Science Center, Houston, Texas (S.L., S.S.)
1,1-Bis-(3'-indolyl)-1-(p-substitutedphenyl)methanes containing p-trifluoromethyl (DIM-C-pPhCF3), p-t-butyl (DIM-C-pPhtBu), and phenyl (DIM-C-pPhC6H5) substituents decrease survival of HCT-116 colon cancer cells and activate peroxisome proliferator-activated receptor (PPAR) 
in this and other cancer cell lines. These PPAR-active compounds had minimal effects on expression of cell cycle proteins and did not induce caveolin-1 in HCT-116 cells. However, these compounds induced nonsteroidal anti-inflammatory drug-activated gene-1 (NAG-1) and apoptosis in HCT-116 cells, and in time-course studies, the PPAR agonists maximally induced early growth response-1 (Egr-1) protein within 2 h, whereas a longer time course was observed for induction of NAG-1 protein. These data, coupled with deletion and mutation analysis of both the Egr-1 and NAG-1 gene promoters, indicate that activation of NAG-1 by these compounds was dependent on prior induction of Egr-1, and induction of these responses was PPAR-independent. Results of kinase inhibitor studies also demonstrated that activation of Egr-1/NAG-1 by methylene-substituted diindolylmethanes (C-DIMs) was phosphatidylinositol 3-kinase-dependent, and this represents a novel receptor-independent pathway for C-DIM-induced growth inhibition and apoptosis in colon cancer cells.
Address correspondence to: Dr. Stephen Safe, Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843-4466. E-mail: ssafe{at}cvm.tamu.edu
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