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Apoptosis‐inducing Factor Maintains the Transformed State of Carcinoma Cells and Represents a New Type of Cancer Drug Target
Author(s) -
Porter Alan G,
Lakshmanan Umayal,
Choo Poh Heok,
Kwan Jair,
Ng Poh Yong,
Guo Ke,
Dhakshinamoorthy Saravanakumar,
Urbano Alexander
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.4.a508-b
Subject(s) - apoptosis inducing factor , apoptosis , transfection , mitochondrion , reactive oxygen species , cancer cell , microbiology and biotechnology , chemistry , programmed cell death , biology , cancer research , cancer , biochemistry , gene , genetics , caspase
Apoptosis inducing factor (AIF) can be released from mitochondria by death stimuli and contributes to DNA degradation. AIF also exhibits reactive oxygen species (ROS)‐generating NADH oxidase activity dispensable for apoptosis. We knocked out the aif gene in human colon carcinoma cells, which displayed lower mitochondrial complex I oxidoreductase activity and produced less ROS, but showed increased sensitivity to peroxide‐ or cancer 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. Anti‐oxidants sensitized AIF‐expressing cells to apoptosis, but had no effect on tumorigenicity. Thus, AIF‐mediated resistance to chemical stress involves elevated levels of ROS found in tumour cells 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. AIF represents a novel type of cancer drug target. (This study was supported by funds from A*Star, Singapore).