G Huang, Y Chen, H Lu, and X Cao.
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-β/RA-induced cancer cell death. We found that IFN-β/RA/RA up-regulates expression of MRC complex subunits. Mitochondrial-nuclear translocation of these subunits was not observed, but overproduction of ROS, which causes loss of mitochondrial function, was detected upon IFN-β/RA/RA treatment. Knockdown of GRIM-19 and NDUFS3, two subunits of MRC complex I, by siRNA in two cancer cell lines conferred resistance to IFN-IFN-β/RA/RA-induced apoptosis and reduced ROS production. In parallel, expression of late genes induced by IFN-β/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-β/RA-induced cell death by modulating ROS production and late gene expression.
Published Cell Death Differ. 2007 Feb. Vol. 14: 327-337.