KUD773, a phenylthiazole derivative, displays anticancer activity in human hormone-refractory prostate cancers through inhibition of tubulin polymerization and anti-Aurora a activity
Journal
Journal of Biomedical Science
Journal Volume
22
Journal Issue
1
Pages
2
Date Issued
2015
Author(s)
Abstract
Background: Hormone-refractory prostate cancer (HRPC), which is resistant to hormone therapy, is a major obstacle in clinical treatment. An approach to inhibit HRPC growth and ultimately to kill cancers is highly demanded. Results: KUD773 induced the anti-proliferative effect and subsequent apoptosis in PC-3 and DU-145 (two HRPC cell lines); whereas, it showed less active in normal prostate cells. Further examination showed that KUD773 inhibited tubulin polymerization and induced an increase of mitotic phosphoproteins and polo-like kinase 1 (PLK1) phosphorylation, indicating a mitotic arrest of the cell cycle through an anti-tubulin action. The kinase assay demonstrated that KUD773 inhibited Aurora A activity. KUD773 induced an increase of Cdk1 phosphorylation at Thr161 (a stimulatory phosphorylation site) and a decrease of phosphorylation at Tyr15 (an inhibitory phosphorylation site), suggesting the activation of Cdk1. The data were substantiated by an up-regulation of cyclin B1 (a Cdk1 partner). Furthermore, KUD773 induced the phosphorylation and subsequent down-regulation of Bcl-2 and activation of caspase cascades. Conclusions: The data suggest that KUD773 induces apoptotic signaling in a sequential manner. It inhibits tubulin polymerization associated with an anti-Aurora A activity, leading to Cdk1 activation and mitotic arrest of the cell cycle that in turn induces Bcl-2 degradation and a subsequent caspase activation in HRPCs. ? 2015 Yu et al.; licensee BioMed Central.
SDGs
Other Subjects
2 (1h imidazol 1 yl) 4 [3 (trifluoromethyl)phenyl]thiazole; aurora A kinase; caspase; cyclin B1; gelatinase A; gelatinase B; phosphoprotein; polo like kinase 1; protein bcl 2; thiazole derivative; unclassified drug; antineoplastic agent; AURKA protein, human; aurora A kinase; thiazole derivative; tubulin; tubulin modulator; antineoplastic activity; antiproliferative activity; apoptosis; Article; castration resistant prostate cancer; cell cycle progression; controlled study; down regulation; drug mechanism; enzyme phosphorylation; human; human cell; male; microtubule assembly; mitosis inhibition; priority journal; protein expression; upregulation; cell cycle; cell line; drug effects; metabolism; polymerization; Prostatic Hyperplasia; Prostatic Neoplasms; Antineoplastic Agents; Apoptosis; Aurora Kinase A; Cell Cycle; Cell Line; Humans; Male; Polymerization; Prostatic Hyperplasia; Prostatic Neoplasms; Thiazoles; Tubulin; Tubulin Modulators
Publisher
BioMed Central Ltd.
Type
journal article