Coupling mitochondrial respiratory chain to cell death: an essential role of mitochondrial complex I in the interferon-beta and retinoic acid-induced cancer cell death.
Combination of retinoic acids (RAs) and interferons (IFNs) has synergistic apoptotic effects and is used in cancer treatment. However, the underlying mechanisms remain unknown. Here, we demonstrate that mitochondrial respiratory chain (MRC) plays an essential role in the IFN-beta/RA-induced cancer cell death. We found that IFN-beta/RA upregulates the expression of MRC complex subunits. Mitochondrial-nuclear translocation of these subunits was not observed, but overproduction of reactive oxygen species (ROS), which causes loss of mitochondrial function, was detected upon IFN-beta/RA treatment. Knockdown of GRIM-19 (gene associated with retinoid-interferon-induced mortality-19) and NDUFS3 (NADH dehydrogenase (ubiquinone) Fe-S protein 3), two subunits of MRC complex I, by siRNA in two cancer cell lines conferred resistance to IFN-beta/RA-induced apoptosis and reduced ROS production. In parallel, expression of late genes induced by IFN-beta/RA that are directly involved in growth inhibition and cell death was also repressed in the knockdown cells. Our data suggest that the MRC regulates IFN-beta/RA-induced cell death by modulating ROS production and late gene expression.
Huang
G
G
Signal Transduction Laboratory, Institute of Molecular and Cell Biology, Singapore, Republic of Singapore.
Chen
Y
Y
Lu
H
H
Cao
X
X
D051017:Apoptosis Regulatory Proteins / Q000172:deficiency / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002467:Cell Nucleus / Q000187:drug effects; D003593:Cytoplasm / Q000187:drug effects; D004357:Drug Synergism; D004579:Electron Transport / Q000187:drug effects; D042967:Electron Transport Complex I / Q000378:metabolism*; D015870:Gene Expression / Q000187:drug effects; D006367:HeLa Cells; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology*; D008928:Mitochondria / Q000187:drug effects; D008954:Models, Biological; D009245:NADH Dehydrogenase / Q000172:deficiency / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000172:deficiency / Q000378:metabolism; D009369:Neoplasms / Q000473:pathology*; D021122:Protein Subunits / Q000378:metabolism; D021381:Protein Transport / Q000187:drug effects; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D014212:Tretinoin / Q000494:pharmacology*; D015854:Up-Regulation / Q000187:drug effects
D051017:Apoptosis Regulatory Proteins; D021122:Protein Subunits; D017382:Reactive Oxygen Species; D014212:Tretinoin; D016899:Interferon-beta; D009247:NADH, NADPH Oxidoreductases; C439057:NDUFA13 protein, human; D009245:NADH Dehydrogenase; D042967:Electron Transport Complex I; C472512:NDUFS3 protein, human