YC-1 suppresses constitutive nuclear factor-κB activation and induces apoptosis in human prostate cancer cells
Journal
Molecular Cancer Therapeutics
Journal Volume
4
Journal Issue
10
Pages
1628-1635
Date Issued
2005
Author(s)
Abstract
Although the indazole compound, YCA, is reported to exert anticancer activities in several cancer cell types, its target and mechanism of action have not been well explored. The objectives of this study were to ascertain whether YC-1 directly induces apoptosis in prostate cancer cells and to explore the mechanism(s) whereby YC-1 causes cell death. Hormone-refractory metastatic human prostate cancer PC-3 cells were selected for this study. 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyl-tetrazolium bromide assay indicated that YC-1 suppresses growth of PC-3 cells in a concentration-dependent and time-dependent manner. Apoptosis was determined using 4′,6-diamidino-2-phenylindole staining, and cell cycle progression was examined by FACScan flow cytometry. YC-1 treatment showed chromatin condensation and increased the percentage of PC-3 cells in the hypodiploid sub-G0-G1 phase, indicative of apoptosis. Additionally, exposure to YC-1 was found to induce activation of caspase-3 and cleavage of poly(ADP-ribose) polymerase. Translocation and activation of nuclear factor-κB (NF-κB) were determined by immunofluorescent staining and ELISA, respectively. The results showed that YC-1 abolished constitutive nuclear translocation and activation of NF-κB/p65. Furthermore, inhibition of inhibitor of κBα (IκBα) phosphorylation and accumulation of IκBα were observed. The antitumor effects of YC-1 were evaluated by measuring the growth of tumor xenografts in YC-1-treated severe combined immunodeficient mice. The volumes of PC-3 tumors produced in severe combined immunodeficient mice were observed to decline significantly after treatment with YCA compared with vehicle controls. We concluded that the antitumor effects of YC-1 in PC-3 cells include the induction of apoptosis and the suppression of NF-κB activation. Given these unique actions, further investigations of the effects of YC-1 against hormone-refractory prostate cancer are warranted. Copyright ? 2005 American Association for Cancer Research.
SDGs
Other Subjects
1 benzyl 3 (5 hydroxymethyl 2 furyl)indazole; 3 (4,5 dimethyl 2 thiazolyl) 2,5 diphenyltetrazolium bromide; 4',6 diamidino 2 phenylindole; I kappa B kinase inhibitor; immunoglobulin enhancer binding protein; nicotinamide adenine dinucleotide adenosine diphosphate ribosyltransferase; synaptotagmin; animal experiment; animal model; animal tissue; antineoplastic activity; apoptosis; article; cancer inhibition; cell cycle; controlled study; drug mechanism; enzyme linked immunosorbent assay; flow cytometry; human; human cell; immunofluorescence; male; metastasis; mouse; nonhuman; priority journal; prostate cancer; Adenocarcinoma; Animals; Apoptosis; Caspase 3; Caspases; Cell Cycle; Cell Line, Tumor; Cell Nucleus; Humans; I-kappa B Proteins; Immunohistochemistry; In Situ Nick-End Labeling; Indazoles; Male; Mice; Mice, SCID; NF-kappa B; Phosphorylation; Prostatic Neoplasms; Transcription Factor RelA; Xenograft Model Antitumor Assays
Type
journal article