TAILIEUCHUNG - Báo cáo khoa học: Chronic high-dose morphine treatment promotes SH-SY5Y cell apoptosis via c-Jun N-terminal kinase-mediated activation of mitochondria-dependent pathway

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. | ễFEBS Journal Chronic high-dose morphine treatment promotes SH-SY5Y cell apoptosis via c-Jun N-terminal kinase-mediated activation of mitochondria-dependent pathway Xin Lin1 z Yu-Jun Wang2 z Qing Li2 Yuan-Yuan Hou1 Min-Hua Hong1 Ying-Lin Cao2 Zhi-Qiang Chi1 and Jing-Gen Liu1 1 State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences China 2 Schoolof Life Science and Biopharmaceutics Shenyang PharmaceuticalUniversity China Keywords apoptosis JNK signaling mitochondria morphine ROS Correspondence . Liu State Key Laboratory of Drug Research Shanghai Institute of Materia Medica Chinese Academy of Sciences Shanghai 201203 China Fax 86 21 50807088 Tel 86 21 50807588 E-mail jgliu@ These authors contributed equally to this work Received 4 December 2008 revised 22 January 2009 accepted 28 January 2009 doi 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 antiapop-totic protein Bcl-2. All of these effects of morphine could be suppressed by the JNK inhibitor SP600125 .

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