WJ9708012 exerts anticancer activity through PKC-α related crosstalk of mitochondrial and endoplasmic reticulum stresses in human hormone-refractory prostate cancer cells
Journal
Acta Pharmacologica Sinica
Journal Volume
32
Journal Issue
1
Pages
89-98
Date Issued
2011
Author(s)
Abstract
Aim:To investigate the anticancer mechanism of a methoxyflavanone derivative, WJ9708012, highlighting its role on a crosstalk between endoplasmic reticulum (ER) and mitochondrial stress.Methods:Cell proliferation was examined using sulforhodamine B assay. Cell-cycle progression, Ca 2+ mobilization and mitochondrial membrane potential (Δψ m) were detected using flow cytometric analysis. Protein expression was detected using Western blot.Results:WJ9708012 displayed an antiproliferative and apoptotic activity in human hormone-refractory prostate cancer cells with IC 50 values of 6.4 and 5.3 μmol/L in PC-3 and DU-145 cells. WJ9708012 induced a prompt increase of cytosolic Ca 2+ level and activation of protein kinase C (PKC)-α. The cleavage ofμ-calpain was also induced by WJ9708012. Furthermore, WJ9708012 induced cell-cycle arrest at G 1-phase associated with down-regulation of cyclin D1, cyclin E and cyclin-dependent kinase-4 expressions. It also caused a rapid and time-dependent decrease of phosphorylation level of mTOR (Ser 2448), 4E-BP1 (Thr 37 /Thr 46 /Thr 70) and p70S6K (Thr 389+), indicating the inhibition of mTOR-mediated translational pathways. The ER stress was activated by the identification of up-regulated GADD153 and glucose-regulated protein-78 protein levels. The subsequent mitochondrial stress was also identified by the observation of a decreased Bcl-2 and Bcl-xL expressions, an increased truncated Bid and Bad and a loss of Δψ m.Conclusion:WJ9708012 induces an increase of cytosolic Ca 2+ concentration and activation of PKC-α. Subsequently, a crosstalk between ER stress and mitochondrial insult is induced, leading to the inhibition of mTOR pathways and arrest of the cell-cycle at G 1 phase. The apoptosis is ultimately induced by a severe damage of mitochondrial function. ? 2011 CPS and SIMM All rights reserved.
Subjects
Ca 2+ mobilization; endoplasmic reticulum tress; methoxyflavanone; mitochondrial stress; protein kinase C-α
SDGs
Other Subjects
6 (3 hydroxy 3 methylbutyl) 2' (7 hydroxy 3,7 dimethyloctyl) 3',4',5,7 tetramethoxyflavanone; antineoplastic agent; calcium ion; calpain 1; cyclin D1; cyclin dependent kinase 4; cyclin E; flavanone derivative; glucose regulated protein 78; growth arrest and DNA damage inducible protein 153; initiation factor 4E binding protein 1; mammalian target of rapamycin; paclitaxel; protein bcl 2; protein bcl xl; protein kinase C alpha; S6 kinase; unclassified drug; wj 9708012; antineoplastic activity; apoptosis; article; calcium cell level; calcium mobilization; cancer cell; cell cycle arrest; cell cycle G1 phase; cell cycle progression; cell growth; cell proliferation; cell stress; controlled study; down regulation; drug mechanism; endoplasmic reticulum stress; enzyme activity; human; human cell; IC 50; male; mitochondrial membrane potential; mitochondrial stress; mitochondrion; protein expression; protein phosphorylation; time; Antineoplastic Agents; Apoptosis; Calcium; Cell Line, Tumor; Cell Proliferation; Endoplasmic Reticulum; Flavones; Gene Expression Regulation, Neoplastic; Humans; Male; Mitochondria; Prostatic Neoplasms; Protein Kinase C-alpha; Signal Transduction; TOR Serine-Threonine Kinases
Type
journal article