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Introduction: Kinetochores anchor microtubules to chromosomes during mitosis and without proper attachment, cell division is arrested at the mitotic checkpoint. In vitro prostate cancer cell viability assays have revealed a cell growth arrest phenomenon following treatment with cyclooxygenase-2 (COX-2) inhibitors. We hypothesized that treatment of prostate cancer cells with COX-2 inhibitors will arrest cell growth at mitosis through regulation of kinetochore proteins.
Materials & Methods: LNCaP and PC3 prostate cancer cells were cultured and treated with a COX-2 inhibitor, celecoxib, a highly-selective COX-2 inhibitor, CAY10404, and a celecoxib analogue without COX-2 inhibition, OSU03012. Cells were lysed at 48 hours and probed for kineotchore proteins: CENP-A, PlK1, and ZWINT. Immunofluorescence (IF) was performed using antibodies to CENP-B, DNA, and tubulin in treated and untreated cells. Additional cells were treated with COX-2 inhibitors and kinase inhibitors to investigate the mechanism of action.
Results: Inhibition of COX-2 by celecoxib and CAY10404 induced a dramatic down-regulation of the kinetochore proteins in LNCaP cells. OSU03012 had no effect. IF staining showed that treatment with COX-2 inhibitors diminished kinetochore structure and blocked mitosis in LNCaP cells. Mixed Results from co-treatment with COX-2 inhibitors and MAP kinase inhibitors suggest a complex mechanism involving MAP kinase pathways.
Conclusions: COX-2 inhibition of prostate cancer cells down-regulates kinetochore protein levels leading to mitotic arrest. These Results correlate with recent epidemiologic studies showing a reduced incidence of prostate cancer among men taking COX-2 inhibitors. Further studies are needed to determine the chemopreventative and chemotherapeutic potential of celecoxib in human prostate cancer.