¹Signal Transduction Laboratory, Institute of Molecular and Cell Biology, Singapore, Republic of Singapore

Correspondence: X Cao, Signal Transduction Laboratory, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos Building, Singapore 138673, Republic of Singapore. Tel: +65-65869657; Fax: +65-67791117; E-mail: mcbcaoxm@imcb.a-star.edu.sg

Received 22 February 2006; Revised 17 May 2006; Accepted 29 May 2006; Published online 7 July 2006.

Abstract

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-/RA-induced cancer cell death. We found that IFN-/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-/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-/RA-induced apoptosis and reduced ROS production. In parallel, expression of late genes induced by IFN-/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-/RA-induced cell death by modulating ROS production and late gene expression.