AIF suppresses chemical stress-induced apoptosis and maintains the transformed state of tumor cells.
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.
Cell Death and Human Disease Group, Institute of Molecular and Cell Biology, Proteos, Republic of Singapore.
Alexander
A
Urbano
Umayal
U
Lakshmanan
Poh Heok
PH
Choo
Jair Chau
JC
Kwan
Poh Yong
PY
Ng
Ke
K
Guo
Saravanakumar
S
Dhakshinamoorthy
Alan
A
Porter
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D051033:Apoptosis Inducing Factor; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D004249:DNA Damage; D042967:Electron Transport Complex I / Q000378:metabolism / Q000502:physiology*; D005420:Flavoproteins / Q000502:physiology*; D006801:Humans; D008565:Membrane Proteins / Q000172:deficiency / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000201:enzymology; D009097:Multienzyme Complexes / Q000378:metabolism; D009247:NADH, NADPH Oxidoreductases / Q000378:metabolism; D041681:NIH 3T3 Cells; D018384:Oxidative Stress / Q000502:physiology; D017382:Reactive Oxygen Species / Q000378:metabolism; D013481:Superoxides / Q000378:metabolism
C494829:AIFM1 protein, human; D051033:Apoptosis Inducing Factor; D005420:Flavoproteins; D008565:Membrane Proteins; D009097:Multienzyme Complexes; C494830:AIFM1 protein, mouse; D017382:Reactive Oxygen Species; D013481:Superoxides; C023107:NADH oxidase; D009247:NADH, NADPH Oxidoreductases; D042967:Electron Transport Complex I