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Luteolin induces apoptosis through endoplasmic reticulum stress and mitochondrial dysfunction in Neuro-2a mouse neuroblastoma cells.
Eur J Pharmacol. 2011 Oct 01; 668(1-2):115-26.EJ

Abstract

Luteolin, a dietary flavonoid, induces apoptosis in various types of cancer cells. However, its role in neuroblastoma and the underlying mechanisms remain to be elucidated. In the present study, we investigated the molecular mechanisms of the anti-cancer effect of luteolin in Neuro-2a mouse neuroblastoma cells. Luteolin induced apoptotic cell death and activation of caspase-12, -9, and -3, and knockdown of caspase-12 by siRNA transfection reduced luteolin-induced cell death. Luteolin also induced expression of endoplasmic reticulum (ER) stress-associated proteins, including C/EBP homologous protein (CHOP) and glucose-regulated proteins (GRP) 94 and 78, cleavage of ATF6α, and phosphorylation of eIF2α. CHOP knockdown or ER stress inhibitor, 4-phenylbutyric acid, reduced luteolin-induced cell death. These results suggest involvement of ER stress in luteolin-induced neuroblastoma cell death. We then showed that luteolin induced accumulation of reactive oxygen species and that the anti-oxidant N-acetylcysteine reduced luteolin-induced cell death and expression of CHOP and GRP78. We also demonstrated rapid reduction of mitochondrial membrane potential by luteolin, and N-acetylcysteine, as well as 4-phenylbutyric acid or CHOP siRNA transfection ameliorated luteolin-induced late loss, but not early loss of mitochondrial membrane potential. Finally, we showed that luteolin induced activation of mitogen-activated protein kinases such as JNK, p38, and ERK, and inhibitors of mitogen-activated protein kinases reduced luteolin-induced cell death and CHOP expression, as well as mitochondrial Bax translocation and cytochrome c release. Collectively, our results suggest that luteolin induces apoptosis through ER stress and mitochondrial dysfunction in Neuro-2a mouse neuroblastoma cells.

Authors+Show Affiliations

Department of Biochemistry and Molecular Biology, School of Medicine, Medical Science and Engineering Research Center for Bioreaction to Reactive Oxygen Species, Biomedical Science Institute, Kyung Hee University, Seoul 130-701, Republic of Korea.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

21762691

Citation

Choi, A Young, et al. "Luteolin Induces Apoptosis Through Endoplasmic Reticulum Stress and Mitochondrial Dysfunction in Neuro-2a Mouse Neuroblastoma Cells." European Journal of Pharmacology, vol. 668, no. 1-2, 2011, pp. 115-26.
Choi AY, Choi JH, Yoon H, et al. Luteolin induces apoptosis through endoplasmic reticulum stress and mitochondrial dysfunction in Neuro-2a mouse neuroblastoma cells. Eur J Pharmacol. 2011;668(1-2):115-26.
Choi, A. Y., Choi, J. H., Yoon, H., Hwang, K. Y., Noh, M. H., Choe, W., Yoon, K. S., Ha, J., Yeo, E. J., & Kang, I. (2011). Luteolin induces apoptosis through endoplasmic reticulum stress and mitochondrial dysfunction in Neuro-2a mouse neuroblastoma cells. European Journal of Pharmacology, 668(1-2), 115-26. https://doi.org/10.1016/j.ejphar.2011.06.047
Choi AY, et al. Luteolin Induces Apoptosis Through Endoplasmic Reticulum Stress and Mitochondrial Dysfunction in Neuro-2a Mouse Neuroblastoma Cells. Eur J Pharmacol. 2011 Oct 1;668(1-2):115-26. PubMed PMID: 21762691.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Luteolin induces apoptosis through endoplasmic reticulum stress and mitochondrial dysfunction in Neuro-2a mouse neuroblastoma cells. AU - Choi,A Young, AU - Choi,Ji Hyun, AU - Yoon,Hana, AU - Hwang,Keun-Young, AU - Noh,Mi Hee, AU - Choe,Wonchae, AU - Yoon,Kyung-Sik, AU - Ha,Joohun, AU - Yeo,Eui-Ju, AU - Kang,Insug, Y1 - 2011/07/08/ PY - 2011/02/25/received PY - 2011/06/13/revised PY - 2011/06/22/accepted PY - 2011/7/19/entrez PY - 2011/7/19/pubmed PY - 2011/12/28/medline SP - 115 EP - 26 JF - European journal of pharmacology JO - Eur J Pharmacol VL - 668 IS - 1-2 N2 - Luteolin, a dietary flavonoid, induces apoptosis in various types of cancer cells. However, its role in neuroblastoma and the underlying mechanisms remain to be elucidated. In the present study, we investigated the molecular mechanisms of the anti-cancer effect of luteolin in Neuro-2a mouse neuroblastoma cells. Luteolin induced apoptotic cell death and activation of caspase-12, -9, and -3, and knockdown of caspase-12 by siRNA transfection reduced luteolin-induced cell death. Luteolin also induced expression of endoplasmic reticulum (ER) stress-associated proteins, including C/EBP homologous protein (CHOP) and glucose-regulated proteins (GRP) 94 and 78, cleavage of ATF6α, and phosphorylation of eIF2α. CHOP knockdown or ER stress inhibitor, 4-phenylbutyric acid, reduced luteolin-induced cell death. These results suggest involvement of ER stress in luteolin-induced neuroblastoma cell death. We then showed that luteolin induced accumulation of reactive oxygen species and that the anti-oxidant N-acetylcysteine reduced luteolin-induced cell death and expression of CHOP and GRP78. We also demonstrated rapid reduction of mitochondrial membrane potential by luteolin, and N-acetylcysteine, as well as 4-phenylbutyric acid or CHOP siRNA transfection ameliorated luteolin-induced late loss, but not early loss of mitochondrial membrane potential. Finally, we showed that luteolin induced activation of mitogen-activated protein kinases such as JNK, p38, and ERK, and inhibitors of mitogen-activated protein kinases reduced luteolin-induced cell death and CHOP expression, as well as mitochondrial Bax translocation and cytochrome c release. Collectively, our results suggest that luteolin induces apoptosis through ER stress and mitochondrial dysfunction in Neuro-2a mouse neuroblastoma cells. SN - 1879-0712 UR - https://www.unboundmedicine.com/medline/citation/21762691/Luteolin_induces_apoptosis_through_endoplasmic_reticulum_stress_and_mitochondrial_dysfunction_in_Neuro_2a_mouse_neuroblastoma_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0014-2999(11)00754-0 DB - PRIME DP - Unbound Medicine ER -