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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.
Apoptosis. 2017 Sep; 22(9):1079-1097.A

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.

Authors+Show Affiliations

Department of Biochemistry and Molecular Biology, School of Medicine, Medical Research Center for Bioreaction to Reactive Oxygen Species, Biomedical Science Institute, Kyung Hee University, Seoul, 02447, Republic of Korea.Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea.Department of Biomedical Sciences, Graduate School, Kyung Hee University, Seoul, 02447, Republic of Korea.Department of Biochemistry and Molecular Biology, School of Medicine, Medical Research Center for Bioreaction to Reactive Oxygen Species, Biomedical Science Institute, Kyung Hee University, Seoul, 02447, Republic of Korea.Department of Biochemistry and Molecular Biology, School of Medicine, Medical Research Center for Bioreaction to Reactive Oxygen Species, Biomedical Science Institute, Kyung Hee University, Seoul, 02447, Republic of Korea.Department of Biochemistry and Molecular Biology, School of Medicine, Medical Research Center for Bioreaction to Reactive Oxygen Species, Biomedical Science Institute, Kyung Hee University, Seoul, 02447, Republic of Korea.Department of Biochemistry and Molecular Biology, School of Medicine, Medical Research Center for Bioreaction to Reactive Oxygen Species, Biomedical Science Institute, Kyung Hee University, Seoul, 02447, Republic of Korea.Department of Biochemistry, College of Medicine, Gachon University, Incheon, 21999, Republic of Korea. euiju@gachon.ac.kr.Department of Biochemistry and Molecular Biology, School of Medicine, Medical Research Center for Bioreaction to Reactive Oxygen Species, Biomedical Science Institute, Kyung Hee University, Seoul, 02447, Republic of Korea. iskang@khu.ac.kr.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

28647884

Citation

Choi, Ji Hyun, et al. "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." Apoptosis : an International Journal On Programmed Cell Death, vol. 22, no. 9, 2017, pp. 1079-1097.
Choi JH, Jeong YJ, Yu AR, et al. 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. Apoptosis. 2017;22(9):1079-1097.
Choi, J. H., Jeong, Y. J., Yu, A. R., Yoon, K. S., Choe, W., Ha, J., Kim, S. S., Yeo, E. J., & Kang, I. (2017). 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. Apoptosis : an International Journal On Programmed Cell Death, 22(9), 1079-1097. https://doi.org/10.1007/s10495-017-1390-2
Choi JH, et al. 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. Apoptosis. 2017;22(9):1079-1097. PubMed PMID: 28647884.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - 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. AU - Choi,Ji Hyun, AU - Jeong,Yeon Ju, AU - Yu,Ah-Ran, AU - Yoon,Kyung-Sik, AU - Choe,Wonchae, AU - Ha,Joohun, AU - Kim,Sung Soo, AU - Yeo,Eui-Ju, AU - Kang,Insug, PY - 2017/6/26/pubmed PY - 2018/10/3/medline PY - 2017/6/26/entrez KW - Apoptosis KW - ER stress KW - Fluoxetine KW - Histone hyperacetylation KW - MAPKs KW - SK-N-BE(2)-M17 cells SP - 1079 EP - 1097 JF - Apoptosis : an international journal on programmed cell death JO - Apoptosis VL - 22 IS - 9 N2 - 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. SN - 1573-675X UR - https://www.unboundmedicine.com/medline/citation/28647884/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_ L2 - https://doi.org/10.1007/s10495-017-1390-2 DB - PRIME DP - Unbound Medicine ER -