The Mechanism of Sertraline-induced [Ca2+]i Rise in Human PC3 Prostate Cancer Cells.

The effect of sertraline, an antidepressant, on cytosolic-free Ca²⁺ levels ([Ca²⁺]i) in human cancer cells is unclear. This study examined whether sertraline altered basal [Ca²⁺]i levels in suspended PC3 human prostate cancer cells by using fura-2 as a Ca²⁺-sensitive fluorescent probe. At concentrations of 10-150 lM, sertraline induced a [Ca²⁺]i rise in a concentration- dependent fashion. The Ca²⁺signal was reduced partly by removing extracellular Ca²⁺indicating that Ca²⁺entry and release both contributed to the [Ca²⁺]i rise. Sertraline induced Mn²⁺ influx, leading to quench of fura-2 fluorescence suggesting Ca²⁺ influx. This Ca²⁺ influx was inhibited by the suppression of store-operated Ca²⁺ channels or by the modulation of protein kinase C activity. In Ca²⁺-free medium, pre-treatment with the endoplasmic reticulum Ca²⁺ pump inhibitor thapsigargin or 2,5-di-(t-butyl)-1,4-hydroquinone nearly abolished sertraline-induced Ca²⁺release. Conversely, pre-treatment with sertraline greatly reduced the inhibitor-induced [Ca²⁺]i rise, suggesting that sertraline released Ca²⁺from the endoplasmic reticulum. Inhibition of phospholipase C inhibited sertraline-induced [Ca²⁺]i rise. At 20-30 μM, sertraline killed cells in a concentrationdependent manner. The cytotoxic effect of sertraline was enhanced by chelating cytosolic Ca²⁺ with 1,2-bis(2-aminophenoxy) ethane-N,N,N',N'-tetraacetic acid /AM. Annexin V-FITC data suggest that sertraline (20 and 30 μM) evoked apoptosis in a concentration-dependent manner. Together, in PC3 human prostate cancer cells, sertraline induced [Ca²⁺]i rises by causing phospholipase C-dependent Ca²⁺ release from the endoplasmic reticulum and via multiple Ca²⁺ influx pathways that involve store-operated Ca²⁺ channels. Sertraline also induced apoptosis that was not triggered by [Ca²⁺]i rise. [ABSTRACT FROM AUTHOR]