The mechanism of sertraline-induced [Ca ²⁺]i rise in human OC2 oral cancer cells

Effect of sertraline, an antidepressant, on cytosolic free Ca ²⁺+ levels ([Ca ²⁺]i) in human cancer cells is unclear. This study examined if sertraline altered basal [Ca ²⁺]i levels in suspended OC2 human oral cancer by using fura-2 as a Ca ²⁺+-sensitive fluorescent probe. At concentrations of 10-100 μM, sertraline induced a [Ca ²⁺]i rise in a concentration-dependent fashion. The Ca ²⁺+ signal was reduced partly by removing extracellular Ca ²⁺+ indicating that Ca ²⁺+ entry and release both contributed to the [Ca ²⁺]i rise. Sertraline induced Mn2+ influx, leading to quench of fura-2 fluorescence suggesting Ca ²⁺+ influx. This Ca ²⁺+ influx was inhibited by suppression of phospholipase A2, inhibition of store-operated Ca ²⁺+ channels or by modulation of protein kinase C activity. In Ca ²⁺+-free medium, pretreatment with the endoplasmic reticulum Ca ²⁺+ pump inhibitor thapsigargin or 2,5-di-(t-butyl)-1,4- hydroquinone (BHQ) nearly abolished sertraline-induced Ca ²⁺+ release. Conversely, pretreatment with sertraline greatly reduced the inhibitor-induced [Ca ²⁺]i rise, suggesting that sertraline released Ca ²⁺+ from the endoplasmic reticulum. Inhibition of phospholipase C did not change sertraline-induced [Ca ²⁺]i rise. Together, in human oral cancer cells, sertraline induced [Ca ²⁺]i rises by causing phospholipase C-independent Ca ²⁺+ release from the endoplasmic reticulum and Ca ²⁺+ influx via store-operated Ca ²⁺+ channels.