Substantial evidence indicates that the cyclo-oxygenase-2 (COX-2) inhibitor celecoxib, a widely prescribed anti-inflammatory agent, displays anti-tumour effect by sensitizing cancer cells to apoptosis. As part of our effort to understand the mechanism by which celecoxib mediates apoptosis in androgen-independent prostate cancer cells, we investigated its effect on intracellular calcium concentration ([Ca2+]i). Digital ratiometric imaging analysis indicates that exposure of PC-3 cells to celecoxib stimulates an immediate [Ca2+]i rise in a dose- and time-dependent manner. Kinetic data show that this Ca2+ signal arises from internal Ca2+ release in conjunction with external Ca2+ influx. Examinations of the biochemical mechanism responsible for this Ca2+ mobilization indicate that celecoxib blocks endoplasmic reticulum (ER) Ca2+-ATPases. Consequently, inhibition of this Ca2+ reuptake mechanism results in Ca2+ mobilization from ER stores followed by capacitative calcium entry, leading to [Ca2+]i elevation. In view of the important role of Ca2+ in apoptosis regulation, this Ca2+ perturbation may represent part of the signalling mechanism that celecoxib uses to trigger rapid apoptotic death in cancer cells. This Ca2+-ATPase inhibitory activity is highly specific for celecoxib, and is not noted with other COX inhibitors tested, including aspirin, ibuprofen, naproxen, rofecoxib (Vioxx®); DuP697 and NS398. Moreover, it is noteworthy that this activity is also observed in many other cell lines examined, including ATr5 smooth muscle cells, NIH 3T3 fibroblast cells and Jurkat T cells. Consequently, this Ca2+-perturbing effect may provide a plausible link with the reported toxicities of celecoxib such as increased cardiovascular risks in long-term anti-inflammatory therapy.
- PC-3 prostate cancer cell