PMID- 26454217 OWN - NLM STAT- MEDLINE DCOM- 20160427 LR - 20211203 IS - 1872-7980 (Electronic) IS - 0304-3835 (Linking) VI - 370 IP - 1 DP - 2016 Jan 1 TI - Honokiol induces autophagy of neuroblastoma cells through activating the PI3K/Akt/mTOR and endoplasmic reticular stress/ERK1/2 signaling pathways and suppressing cell migration. PG - 66-77 LID - S0304-3835(15)00617-5 [pii] LID - 10.1016/j.canlet.2015.08.030 [doi] AB - In children, neuroblastomas are the most common and deadly solid tumor. Our previous study showed that honokiol, a small-molecule polyphenol, can traverse the blood-brain barrier and kill neuroblastoma cells. In this study, we further investigated the mechanisms of honokiol-induced insults to neuroblastoma cells. Treatment of neuroblastoma neuro-2a cells with honokiol elevated the levels of microtubule-associated protein light chain 3 (LC3)-II and induced cell autophagy in time- and concentration-dependent manners. Interestingly, pretreatment with 3-methyladenine (3-MA), an inhibitor of autophagy, led to the simultaneous attenuation of honokiol-induced cell autophagy and apoptosis but did not influence cell necrosis. As to the mechanisms, exposure of neuro-2a cells to honokiol time-dependently decreased the amount of phosphatidylinositol 3-kinase (PI3K). Sequentially, honokiol downregulated phosphorylation of protein kinase B (Akt) and mammalian target of rapamycin (mTOR) in neuro-2a cells. Furthermore, honokiol elevated the levels of glucose-regulated protein (GpR)78, an endoplasmic reticular stress (ERS)-associated protein, and amounts of intracellular reactive oxygen species (ROS). In contrast, reducing production of intracellular ROS using N-acetylcysteine, a scavenger of ROS, concurrently suppressed honokiol-induced cellular autophagy. Consequently, honokiol stimulated phosphorylation of extracellular signal-regulated kinase (ERK)1/2. However, pretreatment of neuro-2a cells with PD98059, an inhibitor of ERK1/2, lowered honokiol-induced autophagy. The effects of honokiol on inducing autophagy and apoptosis of neuroblastoma cells were further confirmed using mouse neuroblastoma NB41A3 cells as our experimental model. Fascinatingly, treatment of neuroblastoma neuro-2a and NB41A3 cells with honokiol for 12 h did not affect cell autophagy or apoptosis but caused significant suppression of cell migration. Taken together, this study showed that honokiol can induce autophagy of neuroblastoma cells and consequent apoptosis through activating the PI3K/Akt/mTOR and ERS/ROS/ERK1/2 signaling pathways and suppressing cell migration. Thus, honokiol has potential for treating neuroblastomas. CI - Copyright (c) 2015 Elsevier Ireland Ltd. All rights reserved. FAU - Yeh, Poh-Shiow AU - Yeh PS AD - Department of Neurology, Chi Mei Medical Center, Tainan, Taiwan; Brain Disease Research Center, Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan. FAU - Wang, Weu AU - Wang W AD - Division of General Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei, Taiwan. FAU - Chang, Ya-An AU - Chang YA AD - Comprehensive Cancer Center and Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan. FAU - Lin, Chien-Ju AU - Lin CJ AD - Comprehensive Cancer Center and Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan. FAU - Wang, Jhi-Joung AU - Wang JJ AD - Department of Anesthesiology, Chi Mei Medical Center, Tainan, Taiwan. FAU - Chen, Ruei-Ming AU - Chen RM AD - Brain Disease Research Center, Wan-Fang Hospital, Taipei Medical University, Taipei, Taiwan; Comprehensive Cancer Center and Graduate Institute of Medical Sciences, Taipei Medical University, Taipei, Taiwan; Anesthetics and Toxicology Research Center, Taipei Medical University Hospital, Taipei, Taiwan. Electronic address: rmchen@tmu.edu.tw. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't DEP - 20151021 PL - Ireland TA - Cancer Lett JT - Cancer letters JID - 7600053 RN - 0 (Biphenyl Compounds) RN - 0 (Lignans) RN - 0 (Reactive Oxygen Species) RN - 11513CCO0N (honokiol) RN - EC 2.7.1.1 (MTOR protein, human) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 2.7.11.24 (Extracellular Signal-Regulated MAP Kinases) SB - IM MH - Animals MH - Apoptosis/drug effects MH - Autophagy/*drug effects MH - Biphenyl Compounds/*pharmacology MH - Cell Line, Tumor MH - Cell Movement/drug effects MH - Endoplasmic Reticulum Stress/*physiology MH - Extracellular Signal-Regulated MAP Kinases/*physiology MH - Humans MH - Lignans/*pharmacology MH - Mice MH - Neuroblastoma/*drug therapy/metabolism/pathology MH - Phosphatidylinositol 3-Kinases/*physiology MH - Proto-Oncogene Proteins c-akt/*physiology MH - Reactive Oxygen Species/metabolism MH - Signal Transduction/drug effects MH - TOR Serine-Threonine Kinases/*physiology OTO - NOTNLM OT - Apoptosis OT - Autophagy OT - Cell migration OT - Honokiol OT - Mechanisms OT - Neuroblastoma EDAT- 2015/10/11 06:00 MHDA- 2016/04/28 06:00 CRDT- 2015/10/11 06:00 PHST- 2015/07/28 00:00 [received] PHST- 2015/08/23 00:00 [revised] PHST- 2015/08/25 00:00 [accepted] PHST- 2015/10/11 06:00 [entrez] PHST- 2015/10/11 06:00 [pubmed] PHST- 2016/04/28 06:00 [medline] AID - S0304-3835(15)00617-5 [pii] AID - 10.1016/j.canlet.2015.08.030 [doi] PST - ppublish SO - Cancer Lett. 2016 Jan 1;370(1):66-77. doi: 10.1016/j.canlet.2015.08.030. Epub 2015 Oct 21.