title: Potential autophagy enhancers protect against fipronil-induced apoptosis in SH-SY5Y cells.
abstract: Oxidative stress created by environmental toxicants activates several signaling pathways. Autophagy is one of the first lines of defense against oxidative stress damage. The autophagy pathway can be induced and up-regulated in response to intracellular reactive oxygen species (ROS). Recently, we reported that fipronil (FPN)-induced mitochondria-dependent apoptosis is mediated through ROS in human neuroblastoma SH-SY5Y cells. In this study, we explored the role of autophagy to prevent FPN neurotoxicity. We investigated the modulation of FPN-induced apoptosis according to autophagy regulation. FPN activated caspase-9 and caspase-3, and induced nuclear fragmentation and condensation, all of which indicate that FPN-induced cell death was due to apoptosis. In addition, we observed FPN-induced autophagic cell death by monitoring the expression of LC3-II and Beclin-1. Exposure to FPN in SH-SY5Y cells led to the production of ROS. Treatment with N-acetyl-cysteine (NAC) effectively blocked both apoptosis and autophagy. Interestingly, pretreatment with rapamycin, an autophagy inducer, significantly enhanced the viability of FPN-exposed cells; the enhancement of cell viability was partially due to alleviation of FPN-induced apoptosis via a decrease in levels of cleaved caspase-3. However, pretreatment with 3-methyladenine (3MA) a specific inhibitor for autophagy, remarkably strengthened FPN toxicity and further induced activation of caspase-3 in these cells. Our studies suggest that FPN-induced cytotoxicity is modified by autophagy regulation and that rapamycin is neuroprotective against FPN-induced apoptosis through enhancing autophagy.
authors.affiliation: Department of Pharmacology, College of Medicine, Hanyang University, Seoul, Republic of Korea; Hanyang Biomedical Research Institute, Seoul, Republic of Korea; Graduate School of Biomedical Science and Engineering, Hanyang University, Seoul, Republic of Korea.
authors.forename: Jae Hyeon
authors.initials: JH
authors.lastname: Park
authors.forename: Jeong Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: Soo-Jin
authors.initials: SJ
authors.lastname: Lee
authors.forename: Soo Jin
authors.initials: SJ
authors.lastname: Park
authors.forename: Kyung Hun
authors.initials: KH
authors.lastname: Park
authors.forename: Mihye
authors.initials: M
authors.lastname: Jeong
authors.forename: Hyun Chul
authors.initials: HC
authors.lastname: Koh
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D001343:Autophagy / Q000187:drug effects*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004347:Drug Interactions; D006801:Humans; D007306:Insecticides / Q000633:toxicity; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects*; D011720:Pyrazoles / Q000037:antagonists & inhibitors / Q000633:toxicity*; D020123:Sirolimus / Q000494:pharmacology*
chemical_list: D007306:Insecticides; D011720:Pyrazoles; D007770:L-Lactate Dehydrogenase; C082360:fipronil; D020123:Sirolimus
keywords: Apoptosis; Autophagy; Fipronil; Neuroprotection; Rapamycin; Reactive oxygen species