ABSTRACT
trans-Stilbenes induce cytochrome P450 1B1 (CYP1B1) inhibition and cell death. 2,4,3',5' tetramethoxystilbene (TMS), a synthetic trans-stilbene analog, induced apoptotic cell death in PC-3 prostate cancer cells, as evidenced by a decrease in the mitochondrial membrane potential. TMS-induced apoptosis was associated with an increase in the level of cell cycle inhibitor, p27(kip1), through reduction of Akt-mediated Skp2 expression. TMS-induced activation of protein phosphatase 2A (PP2A) inhibited Akt phosphorylation and p27(kip1) expression, indicating that PP2A is involved in the induction of p27(kip1) via Akt inhibition. These results suggest that TMS may inhibit the cell cycle through induction of p27(kip1), leading to apoptotic cell death in PC-3 prostate cancer cells.
Subject(s)
Cyclin-Dependent Kinase Inhibitor p27/biosynthesis , Oncogene Protein v-akt/metabolism , Prostatic Neoplasms/drug therapy , Protein Phosphatase 2/metabolism , Stilbenes/pharmacology , Blotting, Western , Cell Line, Tumor , Cell Proliferation/drug effects , DNA, Complementary/biosynthesis , DNA, Complementary/genetics , Flow Cytometry , Glyceraldehyde-3-Phosphate Dehydrogenases/biosynthesis , Humans , Male , Membrane Potentials/drug effects , Mitochondrial Membranes/drug effects , Oncogene Protein v-akt/genetics , Phosphorylation/drug effects , Prostatic Neoplasms/pathology , RNA, Small Interfering , Reverse Transcriptase Polymerase Chain Reaction , S-Phase Kinase-Associated Proteins/biosynthesis , S-Phase Kinase-Associated Proteins/genetics , TransfectionABSTRACT
trans-Stilbenes have been reported to induce cytochrome P450 1B1 (CYP1B1) inhibition and cell death, however, the molecular mechanisms of the effects are not fully understood. We report here that (1-(2-{3-[2-(2,4-dimethoxy-phenyl)-vinyl]-5-methoxy-phenoxy}ethyl)-1H-imidazole), a synthetic stilbene analog (SA) significantly suppressed TCDD-stimulated CYP1B1 mRNA expression. In HL-60 cells, SA induced apoptosis through activation of p38 MAPK and inactivation of Akt, which in turn activated Bad and mitochondrial death signaling pathway, as evidenced by Bax translocation and cytochrome c release. Expression of dominant negative p38 MAPK or constitutively active Akt significantly prevented cell death and mitochondrial Bax translocation, implicating that p38 MAPK and Akt signaling pathways play crucial roles in stilbene-induced apoptosis of HL-60 cells. These results suggest that SA induces apoptotic cell death as well as CYP1B1 inhibition and may thus be beneficial in cancer prevention.
