Abstract
BackgroundHormone-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.ResultsKUD773 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.ConclusionsThe 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.
Highlights
Hormone-refractory prostate cancer (HRPC), which is resistant to hormone therapy, is a major obstacle in clinical treatment
Sulforhodamine B (SRB), taxol, vincristine, carboxyfluorescein succinimidyl ester (CFSE), 4,6-diamidino-2-phenylindole dihydrochloride (DAPI), propidium iodide (PI) and all other chemical compounds were obtained from SigmaAldrich
Determination of anti-proliferative activity of KUD773 The effect of KUD773 on cell proliferation was examined using SRB assay based on the measurement of cellular protein content
Summary
Hormone-refractory prostate cancer (HRPC), which is resistant to hormone therapy, is a major obstacle in clinical treatment. Tubulin-targeting agents inhibit normal function of mitotic spindle, leading to a halt of the cell cycle at mitotic phase and a subsequent cell death [1,2,3]. Tubulin-targeting agents have been successfully used in cancer chemotherapy against several types of cancers, including breast cancer, ovarian cancer and hormonerefractory prostate cancer (HRPC) [1,4,5]. The toxicities, such as peripheral neuropathy, myelosuppression. The regulation of Aurora A RNA, protein and kinase activity is dependent of cell cycle with peaking in the transition of G2 to mitotic phase [8]. Several lines of evidence show that Aurora A is overexpressed in a wide variety of types of cancers, including hepatocellular
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