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Autophagy regulates chlorpyrifos-induced apoptosis in SH-SY5Y cells.
Toxicol Appl Pharmacol. 2013 Apr 01; 268(1):55-67.TA

Abstract

Recent studies have shown that up-regulation of autophagy may be a tractable therapeutic intervention for clearing disease-causing proteins, including α-synuclein, ubiquitin, and other misfolded or aggregated proteins in pesticide-induced neurodegeneration. In a previous study, we reported that chlorpyrifos (CPF)-induced mitochondria-dependent apoptosis is mediated through reactive oxygen species in SH-SY5Y cells. In this study, we explored a novel pharmacotherapeutic approach to prevent CPF neurotoxicity involving the regulation of autophagy. We investigated the modulation of CPF-induced apoptosis according to autophagy regulation. We found that CPF induced apoptosis in SH-SY5Y cells, as demonstrated by the activation of caspase-3 and nuclear condensation. In addition, we observed that cells treated with CPF underwent autophagic cell death by monitoring the expression of LC3-II and p62. Pretreatment with the autophagy inducer rapamycin significantly enhanced the cell viability of CPF-exposed cells, and the enhancement of cell viability was partially due to alleviation of CPF-induced apoptosis via a decrease in levels of cleaved caspase-3. Specifically, rapamycin pretreatment decreased Bax and increased Bcl-2 expression in mitochondria. In addition, rapamycin significantly decreased cytochrome c release in from mitochondria into the cytosol. However, pretreatment of cells with the autophagy inhibitor, 3-methyladenine (3MA), remarkably increased CPF toxicity in these cells; this with correlated with increased expression of Bax and decreased expression of Bcl-2 in mitochondria. Our results suggest that CPF-induced cytotoxicity is modified by autophagy regulation and that rapamycin protects against CPF-induced apoptosis by enhancing autophagy. Pharmacologic induction of autophagy by rapamycin may be a useful treatment strategy in neurodegenerative disorders.

Authors+Show Affiliations

Department of Pharmacology, Hanyang University, Republic of Korea.No 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

23352508

Citation

Park, Jae Hyeon, et al. "Autophagy Regulates Chlorpyrifos-induced Apoptosis in SH-SY5Y Cells." Toxicology and Applied Pharmacology, vol. 268, no. 1, 2013, pp. 55-67.
Park JH, Lee JE, Shin IC, et al. Autophagy regulates chlorpyrifos-induced apoptosis in SH-SY5Y cells. Toxicol Appl Pharmacol. 2013;268(1):55-67.
Park, J. H., Lee, J. E., Shin, I. C., & Koh, H. C. (2013). Autophagy regulates chlorpyrifos-induced apoptosis in SH-SY5Y cells. Toxicology and Applied Pharmacology, 268(1), 55-67. https://doi.org/10.1016/j.taap.2013.01.013
Park JH, et al. Autophagy Regulates Chlorpyrifos-induced Apoptosis in SH-SY5Y Cells. Toxicol Appl Pharmacol. 2013 Apr 1;268(1):55-67. PubMed PMID: 23352508.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Autophagy regulates chlorpyrifos-induced apoptosis in SH-SY5Y cells. AU - Park,Jae Hyeon, AU - Lee,Jeong Eun, AU - Shin,In Chul, AU - Koh,Hyun Chul, Y1 - 2013/01/23/ PY - 2012/07/19/received PY - 2012/12/28/revised PY - 2013/01/10/accepted PY - 2013/1/29/entrez PY - 2013/1/29/pubmed PY - 2013/7/6/medline SP - 55 EP - 67 JF - Toxicology and applied pharmacology JO - Toxicol. Appl. Pharmacol. VL - 268 IS - 1 N2 - Recent studies have shown that up-regulation of autophagy may be a tractable therapeutic intervention for clearing disease-causing proteins, including α-synuclein, ubiquitin, and other misfolded or aggregated proteins in pesticide-induced neurodegeneration. In a previous study, we reported that chlorpyrifos (CPF)-induced mitochondria-dependent apoptosis is mediated through reactive oxygen species in SH-SY5Y cells. In this study, we explored a novel pharmacotherapeutic approach to prevent CPF neurotoxicity involving the regulation of autophagy. We investigated the modulation of CPF-induced apoptosis according to autophagy regulation. We found that CPF induced apoptosis in SH-SY5Y cells, as demonstrated by the activation of caspase-3 and nuclear condensation. In addition, we observed that cells treated with CPF underwent autophagic cell death by monitoring the expression of LC3-II and p62. Pretreatment with the autophagy inducer rapamycin significantly enhanced the cell viability of CPF-exposed cells, and the enhancement of cell viability was partially due to alleviation of CPF-induced apoptosis via a decrease in levels of cleaved caspase-3. Specifically, rapamycin pretreatment decreased Bax and increased Bcl-2 expression in mitochondria. In addition, rapamycin significantly decreased cytochrome c release in from mitochondria into the cytosol. However, pretreatment of cells with the autophagy inhibitor, 3-methyladenine (3MA), remarkably increased CPF toxicity in these cells; this with correlated with increased expression of Bax and decreased expression of Bcl-2 in mitochondria. Our results suggest that CPF-induced cytotoxicity is modified by autophagy regulation and that rapamycin protects against CPF-induced apoptosis by enhancing autophagy. Pharmacologic induction of autophagy by rapamycin may be a useful treatment strategy in neurodegenerative disorders. SN - 1096-0333 UR - https://www.unboundmedicine.com/medline/citation/23352508/Autophagy_regulates_chlorpyrifos_induced_apoptosis_in_SH_SY5Y_cells_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0041-008X(13)00034-3 DB - PRIME DP - Unbound Medicine ER -