RETRACTED ARTICLE: Fluoxetine induces apoptosis through endoplasmic reticulum stress via mitogen-activated protein kinase activation and histone hyperacetylation in SK-N-BE(2)-M17 human neuroblastoma cells

Abstract

Fluoxetine (FLX) is an antidepressant drug that belongs to the class of selective serotonin reuptake inhibitors. FLX is known to induce apoptosis in multiple types of cancer cells. In this study, the molecular mechanisms underlying the anti-cancer effects of FLX were investigated in SK-N-BE(2)-M17 human neuroblastoma cells. FLX induced apoptotic cell death, activation of caspase-4, -9, and -3, and expression of endoplasmic reticulum (ER) stress-associated proteins, including C/EBP homologous protein (CHOP). Inhibition of ER stress by treatment with the ER stress inhibitors, salubrinal and 4-phenylbutyric acid or CHOP siRNA transfection reduced FLX-induced cell death. FLX induced phosphorylation of mitogen-activated protein kinases (MAPKs) family, p38, JNK, and ERK, and an upstream kinase apoptosis signal kinase 1 (ASK1). Inhibition of MAPKs and ASK1 reduced FLX-induced cell death and CHOP expression. We then showed that FLX reduced mitochondrial membrane potential (MMP) and ER stress inhibitors as well as MAPK inhibitors ameliorated FLX-induced loss of MMP. Interestingly, FLX induced hyperacetylation of histone H3 and H4, upregulation of p300 histone acetyltransferase (HAT), and downregulation of histone deacetylases (HDACs). Treatment with a HAT inhibitor anacardic acid or p300 HAT siRNA transfection blocked FLX-induced apoptosis in SK-N-BE(2)-M17 cells. However, FLX did not induce histone acetylation and anacardic acid had no protective effect on FLX-induced cell death and CHOP expression in MYCN non-amplified SH-SY5Y human neuroblastoma and MYCN knockdowned SK-N-BE(2)-M17 cells. These findings suggest that FLX induces apoptosis in neuroblastoma through ER stress and mitochondrial dysfunction via the ASK1 and MAPK pathways and through histone hyperacetylation in a MYCN-dependent manner.

Endoplasmic Reticulum Stress Contributes to Indomethacin-Induced Glioma Apoptosis

“…Intriguingly, the responses of the other two MAPK members, ERK and JNK, to indomethacin were far less than that observed with p38. Despite the discrepancy, biochemical findings suggested a potential involvement of ER stress in the regulation of p38 signaling since the MAPK upstream kinase Ask1 and free radicals correlated well with ER stress [31,32,35]. This was confirmed by our subsequent findings that showed indomethacin increased protein phosphorylation of PERK and eIF2α, and protein expression of CHOP, indicating the induction of ER stress.…”

“…The generation of reactive oxygen species and mobilization of cytosolic free Ca 2+ are consequences of ER stress, and oxidative stress also acts as an inducer of ER stress [31,32,35]. Elevated levels of reactive oxygen species and cytosolic free Ca 2+ were found in indomethacin-treated glioma cells.…”

“…ER-associated Ask1 is an upstream kinase of p38 [35]. Thus, the crosstalk between ER stress and p38 axis was investigated.…”

Repurposing a psychoactive drug for children with cancer: p27Kip1-dependent inhibition of metastatic neuroblastomas by Prozac

“…Prozac did not cause significant changes in cell cycling activity, but it induced a significant increase of DNA fragmentation in the CKS1/MYC high cell lines Kelly and SKNAS compared to CKS1/MYC low hNB and BJ (Supplementary figure 2). The hypothesis that Prozac might cause apoptosis of neuroblastoma cells is corroborated by a recent study showing that the MYCN-amplified SK-N-BE 2 cell line undergoes apoptosis in the presence of the drug 18 . The selected neuroblastoma cell lines were cultured in the presence of increasing concentrations of Prozac and subjected to western blot analysis with a p27 antibody.…”

The effects of fluoxetine on the human adipose‐derived stem cell proliferation and differentiation

“…Typically, SSRIs are used to treat depression, and FLX is one of the most widely used drugs in this category with fewer side effects compared to other antidepressants [5,26]. Studies reported that FLX might affect fetus development, cancer, apoptosis, inflammation, neurogenesis, neuronal maturation, changes in neurotransmitters (glutamate and noradrenaline), cell proliferation and differentiation [27][28][29][30][31][32][33][34]. In this study, the effects of FLX on proliferation and differentiation of human ADSCs were investigated.…”