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

Abstract

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. © SAGE Publications 2011.