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WJ9708012 exerts anticancer activity through PKC-α related crosstalk of mitochondrial and endoplasmic reticulum stresses in human hormone-refractory prostate cancer cells.

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 of μ-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.

SUBMITTER: Kuo TC

PROVIDER: S-EPMC4003311 | biostudies-other | 2011 Jan

REPOSITORIES: biostudies-other

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Project description:Increasing evidence in substantiating the roles of endoplasmic reticulum stress, oxidative stress, and inflammatory responses and their interplay is evident in various diseases. However, an in-depth mechanistic understanding of the crosstalk between the intracellular stress signaling pathways and inflammatory responses and their participation in disease progression has not yet been explored. Progress has been made in our understanding of the cross talk and integrated stress signaling network between endoplasmic reticulum stress and oxidative stress towards the pathogenesis of diabetic nephropathy. In this present study, we studied the crosstalk between the endoplasmic reticulum stress and oxidative stress by understanding the role of protein disulfide isomerase and endoplasmic reticulum oxidase 1α, a key player in redox protein folding in the endoplasmic reticulum. We had recruited a total of 90 subjects and divided into three groups (control (n = 30), type 2 diabetes mellitus (n = 30), and diabetic nephropathy (n = 30)). We found that endoplasmic reticulum stress markers, activating transcription factor 6, inositol-requiring enzyme 1α, protein kinase RNA-like endoplasmic reticulum kinase, C/EBP homologous protein, and glucose-regulated protein-78; oxidative stress markers, thioredoxin-interacting protein and cytochrome b-245 light chain; and the crosstalk markers, protein disulfide isomerase and endoplasmic reticulum oxidase-1α, were progressively elevated in type 2 diabetes mellitus and diabetic nephropathy subjects. The association between the crosstalk markers showed a positive correlation with endoplasmic reticulum stress and oxidative stress markers. Further, the interplay between endoplasmic reticulum stress and oxidative stress was investigated in vitro using a human leukemic monocytic cell line under a hyperglycemic environment and examined the expression of protein disulfide isomerase and endoplasmic reticulum oxidase-1α. DCFH-DA assay and flow cytometry were performed to detect the production of free radicals. Further, phosphorylation of eIF2α in high glucose-exposed cells was studied using western blot. In conclusion, our results shed light on the crosstalk between endoplasmic reticulum stress and oxidative stress and significantly contribute to the onset and progression of diabetic nephropathy and therefore represent the major therapeutic targets for alleviating micro- and macrovascular complications associated with this metabolic disturbance. Graphical abstract.

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WJ9708012 exerts anticancer activity through PKC-α related crosstalk of mitochondrial and endoplasmic reticulum stresses in human hormone-refractory prostate cancer cells.

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