Methoxychalcone induces cell-cycle arrest and apoptosis in human hormone-resistant prostate cancer cells through PI 3-kinase-independent inhibition of mTOR pathways
Journal
Prostate
Journal Volume
70
Journal Issue
12
Pages
1295-1306
Date Issued
2010
Author(s)
Abstract
BACKGROUND. Chalcones are contained in fruits and vegetables, and have been suggested to display anticancer activities. In this study, the anticancer mechanism of WJ9708011 (a methoxychalcone derivative) was delineated in human prostate cancer cells. METHOD. Cell proliferation was examined by sulforhodamine B and clonogenic assays. Cell-cycle progression and mitochondrial membrane potential (Δψm) were detected by flow cytometric analysis. Expressions of protein and mRNA were detected by Western blot and RT-PCR technique, respectively. The protein synthesis was examined by [ 3H]leucine incorporation assay. The overexpression or knockdown techniques for specific target protein were also used in this study. RESULTS. WJ9708011 induced time- and concentration-dependent G1 arrest of the cell cycle and subsequent apoptosis in human prostate cancer cells. The G1-arrest effect was confirmed by down-regulated expressions of several G1-phase regulators, including cyclin D1, cyclin E, cyclin-dependent kinase (Cdk)-4, Cdk2, phospho-RB, E2F-1, and Cdc25A. The mRNA expressions of cyclin D1 and cyclin E were also inhibited through the suppression of NF-κB. WJ9708011 blocked the protein synthesis and inhibited mammalian target of rapamycin (mTOR) signaling pathways. The suppression of mTOR pathways were irrespective of Akt- and AMPK-activated protein kinase (AMPK), but were attributed to mitochondrial stress, in which the down-regulation of survivin protein level may play a crucial role. CONCLUSIONS. The data suggest that WJ9708011 induces transcriptional and translational suppression of cell-cycle regulators that might be through Akt- and AMPK-independent loss of Δψm and inhibition of mTOR signaling pathway, leading to G1 arrest of the cell cycle and subsequent apoptotic cell death. ? 2010 Wiley-Liss, Inc.
Subjects
G1 arrest; Methoxychalcone; Mitochondrial stress; mTOR; Survivin
SDGs
Other Subjects
chalcone derivative; cyclin D1; cyclin dependent kinase 2; cyclin dependent kinase 4; cyclin E; hydroxymethylglutaryl coenzyme A reductase kinase; immunoglobulin enhancer binding protein; leucine; mammalian target of rapamycin; messenger RNA; phosphatidylinositol 3 kinase; protein kinase B; protein tyrosine phosphatase; retinoblastoma protein; sulforhodamine B; survivin; transcription factor E2F1; unclassified drug; wj 9708011; antineoplastic activity; apoptosis; article; cancer cell culture; cell cycle arrest; cell cycle G1 phase; cell cycle progression; cell proliferation; cell stress; clonogenic assay; concentration response; controlled study; down regulation; enzyme inhibition; flow cytometry; gene expression; gene overexpression; human; human cell; human cell culture; male; mitochondrial membrane potential; mitochondrion; priority journal; prostate cancer; protein expression; protein synthesis; protein targeting; reverse transcription polymerase chain reaction; signal transduction; 1-Phosphatidylinositol 3-Kinase; Apoptosis; Cell Cycle; Cell Division; Chalcones; DNA Damage; DNA Primers; DNA Repair; Humans; Intracellular Signaling Peptides and Proteins; Male; Membrane Potentials; Mitochondria; Prostatic Neoplasms; Protein-Serine-Threonine Kinases; Reactive Oxygen Species; Reverse Transcriptase Polymerase Chain Reaction; RNA, Neoplasm; RNA, Small Interfering; Tumor Cells, Cultured; Tumor Stem Cell Assay
Type
journal article