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The antidepressant fluoxetine induces necrosis by energy depletion and mitochondrial calcium overload

Charles, Emilie
Hammadi, Mehdi
Kischel, Philippe
Delcroix, Vanessa
Vacher, Anne-Marie
Devin, Anne
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Published in Oncotarget. 2016
Abstract Selective Serotonin Reuptake Inhibitor antidepressants, such as fluoxetine (Prozac), have been shown to induce cell death in cancer cells, paving the way for their potential use as cancer therapy. These compounds are able to increase cytosolic calcium concentration ([Ca2+]cyt), but the involved mechanisms and their physiological consequences are still not well understood. Here, we show that fluoxetine induces an increase in [Ca2+]cyt by emptying the endoplasmic reticulum (ER) through the translocon, an ER Ca2+ leakage structure. Our data also show that fluoxetine inhibits oxygen consumption and lowers mitochondrial ATP. This latter is essential for Ca2+ reuptake into the ER, and we postulated therefore that the fluoxetine-induced decrease in mitochondrial ATP production results in the emptying of the ER, leading to capacitative calcium entry. Furthermore, Ca2+ quickly accumulated in the mitochondria, leading to mitochondrial Ca2+ overload and cell death. We found that fluoxetine could induce an early necrosis in human peripheral blood lymphocytes and Jurkat cells, and could also induce late apoptosis, especially in the tumor cell line. These results shed light on fluoxetine-induced cell death and its potential use in cancer treatment.
PMID: 27911858
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Article (Published version) (8.4 MB) - document accessible for UNIGE members only Limited access to UNIGE
Research groups Signaux intracellulaires (210)
Mécanismes de la présentation croisée des antigènes (1011)
Projects FNS: 31003A_149566
FNS: 31003A_169491
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CHARLES, Emilie et al. The antidepressant fluoxetine induces necrosis by energy depletion and mitochondrial calcium overload. In: Oncotarget, 2016. doi: 10.18632/oncotarget.13689 https://archive-ouverte.unige.ch/unige:93334

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Deposited on : 2017-04-07

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