1,1-Bis(3'-indolyl)-1-(p-substitutedphenyl)methanes are peroxisome proliferator-activated receptor gamma 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.
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) gamma in this and other cancer cell lines. These PPARgamma-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 PPARgamma 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 PPARgamma-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.
Chintharlapalli
Sudhakar
S
Deparmtent of Biochemistry and Biphysics, College of Agriculture and Life Sciences, Texas A&M University, College Station, Texas, USA.
Papineni
Sabitha
S
Baek
Seung Joon
SJ
Liu
Shengxi
S
Safe
Stephen
S
D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D016207:Cytokines / Q000235:genetics; D051766:Early Growth Response Protein 1 / Q000235:genetics; D005786:Gene Expression Regulation / Q000187:drug effects; D055436:Growth Differentiation Factor 15; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D047495:PPAR gamma / Q000819:agonists*; D019869:Phosphatidylinositol 3-Kinases; D011401:Promoter Regions, Genetic
C505817:1,1-bis(3'-indolyl)-1-(4-biphenyl)methane; C505816:1,1-bis(3'-indolyl)-1-(4-t-butylphenyl)methane; C492909:1,1-bis(3'-indolyl)-1-(4-trifluoromethylphenyl)methane; D016207:Cytokines; C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; C526140:GDF15 protein, human; D055436:Growth Differentiation Factor 15; D007211:Indoles; D047495:PPAR gamma; D019869:Phosphatidylinositol 3-Kinases