Article
- The EMBO Journal (2005) 24, 2815 - 2826
- doi:10.1038/sj.emboj.7600746
Published online: 7 July 2005
Subject Categories:
AIF suppresses chemical stress-induced apoptosis and maintains the transformed state of tumor cells
Alexander Urbano1, Umayal Lakshmanan1, Poh Heok Choo1, Jair Chau Kwan1, Poh Yong Ng1, Ke Guo2, Saravanakumar Dhakshinamoorthy1 and Alan Porter1
- Cell Death and Human Disease Group, Institute of Molecular and Cell Biology, Proteos, Singapore, Republic of Singapore
- Histology Unit, Institute of Molecular and Cell Biology, Proteos, Singapore, Republic of Singapore
Correspondence to:
Alan Porter, Cell Death and Human Disease Group, Institute of Molecular and Cell Biology, 61 Biopolis Drive, Proteos, Singapore 138673, Republic of Singapore. Tel.: +65 6586 9675; Fax: +65 6779 1117; E-mail: mcbagp@imcb.a-star.edu.sg
Received 7 February 2005; Accepted 16 June 2005
Abstract
Apoptosis-inducing factor (AIF) exhibits reactive oxygen species (ROS)-generating NADH oxidase activity of unknown significance, which is dispensable for apoptosis. We knocked out the aif gene in two human colon carcinoma cell lines that displayed lower mitochondrial complex I oxidoreductase activity and produced less ROS, but showed increased sensitivity to peroxide- or drug-induced apoptosis. AIF knockout cells failed to form tumors in athymic mice or grow in soft agar. Only AIF with intact NADH oxidase activity restored complex I activity and anchorage-independent growth of aif knockout cells, and induced aif-transfected mouse NIH3T3 cells to form foci. AIF knockdown in different carcinoma cell types resulted in lower superoxide levels, enhanced apoptosis sensitivity and loss of tumorigenicity. Antioxidants sensitized AIF-expressing cells to apoptosis, but had no effect on tumorigenicity. In summary, AIF-mediated resistance to chemical stress involves ROS and probably also mitochondrial complex I. AIF maintains the transformed state of colon cancer cells through its NADH oxidase activity, by mechanisms that involve complex I function. On both counts, AIF represents a novel type of cancer drug target.
Keywords:
- AIF,
- apoptosis,
- colon cancer,
- NADH oxidase,
- tumorigenesis
MORE ARTICLES LIKE THIS
These links to content published by NPG are automatically generated
REVIEWS
Trashing the genome: the role of nucleases during apoptosis
Nature Reviews Molecular Cell Biology Review (01 Sep 2005)
No death without life: vital functions of apoptotic effectors
Cell Death and Differentiation Review
RESEARCH
AIF deficiency compromises oxidative phosphorylation
The EMBO Journal Article (24 Nov 2004)
The harlequin mouse mutation downregulates apoptosis-inducing factor
Nature Article (26 Sep 2002)
Physical interaction of apoptosis-inducing factor with DNA and RNA
Oncogene Original Article
