Chronic high-dose morphine treatment promotes SH-SY5Y cell apoptosis via c-Jun N-terminal kinase-mediated activation of mitochondria-dependent pathway

doi:10.1111/j.1742-4658.2009.06938.x

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	Chronic high-dose morphine treatment promotes SH-SY5Y cell apoptosis via c-Jun N-terminal kinase-mediated activation of mitochondria-dependent pathway
	Lin, Xin 1; Wang, Yu-Jun2 ; Li, Qing 2; Hou, Yuan-Yuan 1; Hong, Min-Hua 1; Cao, Ying-Lin 2; Chi, Zhi-Qiang1 ; Liu, Jing-Gen1
刊名	FEBS JOURNAL
	2009-04
卷号	276 期号:7 页码:2022-2036
关键词	apoptosis JNK signaling mitochondria morphine ROS
ISSN号	1742-464X
DOI	10.1111/j.1742-4658.2009.06938.x
文献子类	Article
英文摘要	Chronic high doses of morphine inhibit the growth of various human cancer cell lines. However, the mechanisms by which such high-dose morphine inhibits cell proliferation and induces cell death are not fully understood. Here we show that c-Jun N-terminal kinase (JNK) plays a pivotal role in high-dose morphine-induced apoptosis of SH-SY5Y cells in a mitochondria-dependent manner. Activation of JNK by morphine led to reactive oxygen species (ROS) generation via the mitochondrial permeability transition pore, because the mPTP inhibitor cyclosporin A significantly inhibited ROS generation. ROS in turn exerted feedback regulation on JNK activation, as shown by the observations that cyclosporin A and the antioxidant N-acetylcysteine significantly inhibited the phosphorylation of JNK induced by morphine. ROS-amplified JNK induced cytochrome c release and caspase-9/3 activation through enhancement of expression of the proapoptotic protein Bim and reduction of expression of the antiapoptotic protein Bcl-2. All of these effects of morphine could be suppressed by the JNK inhibitor SP600125 and N-acetylcysteine. The key role of the JNK pathway in morphine-induced apoptosis was further confirmed by the observation that decreased levels of JNK in cells transfected with specific small interfering RNA resulted in resistance to the proapoptotic effect of morphine. Thus, the present study clearly shows that morphine-induced apoptosis in SH-SY5Y cells involves JNK-dependent activation of the mitochondrial death pathway, and that ROS signaling exerts positive feedback regulation of JNK activity.
资助项目	Ministry of Science and Technology of China[G2003CB515400] ; Ministry of Science and Technology of China[2009CB522000] ; National Natural Science Foundation of China[30425002] ; Chinese Academy of Sciences[KSCXI/YW/R/68]
WOS关键词	HUMAN NEUROBLASTOMA-CELLS ; BCL-2 FAMILY-MEMBERS ; MESSENGER-RNA EXPRESSION ; PROSTATE-CANCER CELLS ; KAPPA-B ACTIVATION ; CYTOCHROME-C ; PERMEABILITY TRANSITION ; NH2-TERMINAL KINASE ; CARDIAC MYOCYTES ; UP-REGULATION
WOS研究方向	Biochemistry & Molecular Biology
语种	英语
出版者	WILEY
WOS记录号	WOS:000264021900020
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/279277]
专题	药理学第二研究室中科院受体结构与功能重点实验室新药研究国家重点实验室
通讯作者	Liu, Jing-Gen
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Shenyang Pharmaceut Univ, Sch Life Sci & Biopharmaceut, Shenyang, Peoples R China
推荐引用方式 GB/T 7714	Lin, Xin,Wang, Yu-Jun,Li, Qing,et al. Chronic high-dose morphine treatment promotes SH-SY5Y cell apoptosis via c-Jun N-terminal kinase-mediated activation of mitochondria-dependent pathway[J]. FEBS JOURNAL,2009,276(7):2022-2036.
APA	Lin, Xin.,Wang, Yu-Jun.,Li, Qing.,Hou, Yuan-Yuan.,Hong, Min-Hua.,...&Liu, Jing-Gen.(2009).Chronic high-dose morphine treatment promotes SH-SY5Y cell apoptosis via c-Jun N-terminal kinase-mediated activation of mitochondria-dependent pathway.FEBS JOURNAL,276(7),2022-2036.
MLA	Lin, Xin,et al."Chronic high-dose morphine treatment promotes SH-SY5Y cell apoptosis via c-Jun N-terminal kinase-mediated activation of mitochondria-dependent pathway".FEBS JOURNAL 276.7(2009):2022-2036.