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Oncogene

Oncogene

IF: 7.3
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Wild-type IDH2 protects nuclear DNA from oxidative damage and is a potential therapeutic target in colorectal cancer

Published:4 August 2021 DOI: 10.1038/s41388-021-01968-2 PMID: 34349242
Shuang Qiao, Wenhua Lu, Christophe Glorieux, Jiangjiang Li, Peiting Zeng, Ning Meng, Huiqin Zhang, Shijun Wen, Peng Huang

Abstract

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.

Substances (8)

Materials
Procduct Name CAS Molecular Formula Supplier Price
Oxaliplatin 61825-94-3 C8H12N2O4Pt 665 suppliers $17.00-$2180.00
Oxaliplatin 61825-94-3 C8H12N2O4Pt 665 suppliers $17.00-$2180.00
Oxaliplatin 61825-94-3 C8H12N2O4Pt 665 suppliers $17.00-$2180.00
Oxaliplatin 61825-94-3 C8H12N2O4Pt 665 suppliers $17.00-$2180.00
KU-60019 925701-49-1 C30H33N3O5S 133 suppliers $35.00-$9435.20
KU-60019 925701-49-1 C30H33N3O5S 133 suppliers $35.00-$9435.20
KU-60019 925701-49-1 C30H33N3O5S 133 suppliers $35.00-$9435.20
KU-60019 925701-49-1 C30H33N3O5S 133 suppliers $35.00-$9435.20

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