p21 Expression Is Induced by Activation of Nuclear Nerve Growth Factor-Induced Bα (Nur77) in Pancreatic Cancer Cells

Abstract

1,1-Bis(3'-indolyl)-1-(p-anisyl)methane (DIM-C-pPhOCH(3)) activates the orphan receptor nerve growth factor-induced B alpha (Nur77) in cancer cells, and in this study, DIM-C-pPhOCH(3) decreased Panc1 pancreatic cancer cell :survival and arrested cells in G(0)-G(1). These responses were accompanied by induction of the cyclin-dependent kinase inhibitor p21 in pancreatic cancer cells. Mechanistic studies showed that induction of p21 mRNA and protein by DIM-C-pPhOCH(3) was Nur77 dependent but did not depend on Kruppel-like factor 4, which was also induced by DIM-C-pPhOCH(3). Activation of p21 promoter constructs by DIM-C-pPhOCH(3) required the GC-rich proximal region of the promoter, and results of RNA interference studies showed that Nur77-dependent activation of the p21 promoter involved interactions with Sp1 and Sp4 but not Spa. Interactions of Nur77 with the p21 promoter in Panc1 cells treated with DIM-C-pPhOCH(3) were also confirmed in chromatin immunoprecipitation assays. These data show that activation of nuclear Nur77 results in a novel pathway for induction of p21, which is independent of Nur77 response elements but dependent on Sp proteins bound to the GC-rich proximal region of the p21 promoter. [Mol Cancer Res 2009;7(7):1169-78]