Overexpression of ornithine decarboxylase suppresses thapsigargin-induced apoptosis.
Ornithine decarboxylase (ODC), the key enzyme of polyamine biosynthesis, has paradoxical roles in apoptosis. Our published papers show overexpression of ODC prevents the apoptosis induced by many cytotoxic drugs. Thapsigargin (TG) is an inhibitor of the sarcoplasmic/endoplasmic reticulum (ER) Ca(2+) ATPase (SERCA) pumps and causes ER stress-induced apoptosis. We used ODC overexpressing cell lines to examine whether overexpression of ODC inhibits TG-induced apoptosis. Our results indicated overexpression of ODC attenuated TG-induced apoptosis. Overexpression of ODC blocked procaspase-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 down-stream caspase activation were blocked. That is, overexpression of ODC inhibits the mitochondria-mediated 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.
Hsieh
Wei-Chung
WC
Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan, ROC.
Hsu
Pei-Chen
PC
Liao
Ya-Fan
YF
Young
Shu-Ting
ST
Wang
Zeng-Wei
ZW
Lin
Chih-Li
CL
Tsay
Gregory J
GJ
Lee
Huei
H
Hung
Hui-Chih
HC
Liu
Guang-Yaw
GY
D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000032:analysis / Q000378:metabolism; D045304:Cytochromes c / Q000032:analysis / Q000378:metabolism; D004721:Endoplasmic Reticulum / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005786:Gene Expression Regulation; D018922:HL-60 Cells; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects / Q000502:physiology; D008928:Mitochondria / Q000378:metabolism; D009955:Ornithine Decarboxylase / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects / Q000502:physiology; D011073:Polyamines / Q000032:analysis / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D019284:Thapsigargin / Q000494:pharmacology*; D051742:Transcription Factor CHOP / Q000037:antagonists & inhibitors / Q000378:metabolism; D050998:bcl-2 Homologous Antagonist-Killer Protein / Q000037:antagonists & inhibitors / Q000378:metabolism; D019892:eIF-2 Kinase / Q000378:metabolism
D061945:Caspase Inhibitors; D020169:Caspases; D045304:Cytochromes c; D004791:Enzyme Inhibitors; D009955:Ornithine Decarboxylase; D011073:Polyamines; D019253:Proto-Oncogene Proteins c-bcl-2; D053498:Sarcoplasmic Reticulum Calcium-Transporting ATPases; D019284:Thapsigargin; D051742:Transcription Factor CHOP; D050998:bcl-2 Homologous Antagonist-Killer Protein; D019892:eIF-2 Kinase; C494772:BAK1 protein, human; C497249:DDIT3 protein, human