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KMID : 0578320100300040311
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Molecules and Cells
2010 Volume.30 No. 4 p.311 ~ p.318
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Overexpression of Ornithine Decarboxylase Suppresses Thapsigargin-Induced Apoptosis
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Wei-Chung Hsieh
Pei-Chen Hsu
Ya-Fan Liao
Shu-Ting Young
Zeng-Wei Wang
Chih-Li Lin
Gregory J. Tsay
Huei Lee
Hui-Chih Hung
Guang-Yaw Liu
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Abstract
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Ornithine decarboxylase (ODC), the key enzyme of polya-mine biosynthesis, has paradoxical roles in apoptosis. Our published papers show overexpression of ODC pre-vents the apoptosis induced by many cytotoxic drugs. Thapsigargin (TG) is an inhibitor of the sarcoplasmic/en-doplasmic reticulum (ER) Ca2+ ATPase (SERCA) pumps and causes ER stress-induced apoptosis. We used ODC overexpressing cell lines to examine whether overexpres-sion of ODC inhibits TG-induced apoptosis. Our results indicated overexpression of ODC attenuated TG-induced apoptosis. Overexpression of ODC blocked procaspse-4 cleavage and phosphorylation of protein kinase-like ER-resident kinase (PERK), triggered by TG. It also attenuated the increase in CAAT/enhancer binding protein homologous protein (CHOP). Cells with overexpressed ODC had greater Bcl-2 expression. Overexpression of ODC preserved the expression of Bcl-2, inhibited the increase in Bak and stabilized mitochondrial membrane potential without the influences of TG. Cytochrome c release and downstream caspase activation were blocked. That is, overexpression of ODC inhibits the mitochondria-medi-ated apoptotic pathway, induced by TG. Finally, overexpression of ODC maintains the protein and mRNA expression of SERCA. In conclusion, overexpression of ODC suppresses TG-induced apoptosis by blocking caspase-4 activation and PERK phosphorylation, attenuating CHOP expression and inhibiting the mitochondria-mediated apoptotic pathway.
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KEYWORD
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endoplasmic reticulum (ER), mitochondrial membrane potential, ornithine decarboxylase (ODC), thapsigargin (TG)
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