Although the role of
isocitrate dehydrogenase (IDH) mutation in promoting
cancer development has been well-characterized, the impact of wild-type IDH on
cancer cells remains unclear. Here we show that the wild-type
isocitrate dehydrogenase 2 (IDH2) is highly expressed in
colorectal cancer (CRC) cells, and plays an unexpected role in protecting the
cancer cells from oxidative damage. Genetic abrogation of IDH2 in CRC cells leads to
reactive oxygen species (ROS)-mediated DNA damage and an accumulation of
8-oxoguanine with
DNA strand breaks, which activates DNA damage response (DDR) with elevated γH2AX and phosphorylation of
ataxia telangiectasia-mutated (
ATM) protein, leading to a partial cell cycle arrest and eventually cell senescence. Mechanistically, the suppression of IDH2 results in a reduction of the
tricarboxylic acid (TCA) cycle activity due to a decrease in the conversion of
isocitrate to α-ketoglutarate (α-KG) with a concurrent decrease in
NADPH production, leading to ROS accumulation and oxidative DNA damage. Importantly, abrogation of IDH2 inhibits CRC cell growth in vitro and in vivo, and renders CRC cells more vulnerable to
DNA-damaging drugs. Screening of an FDA-approved drug library has identified
oxaliplatin as a compound highly effective against CRC cells when IDH2 was suppressed. Our study has uncovered an important role of the wild-type IDH2 in protecting
DNA from oxidative damage, and provides a novel biochemical basis for developing metabolic intervention strategy for
cancer treatment.