Other
15 Authors
- Schrump DS,
- Song NY,
- Su L,
- Sun Z,
- Wu X,
- Johnson PF,
- Xia X,
- Karin M,
- Ma B,
- Xi S,
- Hu Y,
- Nussinov R,
- Zhu F,
- Wang Z,
- Willette-Brown J
| First Author | Song NY | Year | 2018 |
| Journal | Proc Natl Acad Sci U S A | Volume | 115 |
| Issue | 4 | Pages | E812-E821 |
| PubMed ID | 29311298 | Mgi Jnum | J:260592 |
| Mgi Id | MGI:6113759 | Doi | 10.1073/pnas.1717520115 |
| Citation | Song NY, et al. (2018) IKKalpha inactivation promotes Kras-initiated lung adenocarcinoma development through disrupting major redox regulatory pathways. Proc Natl Acad Sci U S A 115(4):E812-E821 |
| abstractText | Lung adenocarcinoma (ADC) and squamous cell carcinoma (SCC) are two distinct and predominant types of human lung cancer. IkappaB kinase alpha (IKKalpha) has been shown to suppress lung SCC development, but its role in ADC is unknown. We found inactivating mutations and homologous or hemizygous deletions in the CHUK locus, which encodes IKKalpha, in human lung ADCs. The CHUK deletions significantly reduced the survival time of patients with lung ADCs harboring KRAS mutations. In mice, lung-specific Ikkalpha ablation (Ikkalpha(DeltaLu) ) induces spontaneous ADCs and promotes Kras(G12D)-initiated ADC development, accompanied by increased cell proliferation, decreased cell senescence, and reactive oxygen species (ROS) accumulation. IKKalpha deletion up-regulates NOX2 and down-regulates NRF2, leading to ROS accumulation and blockade of cell senescence induction, which together accelerate ADC development. Pharmacologic inhibition of NADPH oxidase or ROS impairs Kras(G12D)-mediated ADC development in Ikkalpha(DeltaLu) mice. Therefore, IKKalpha modulates lung ADC development by controlling redox regulatory pathways. This study demonstrates that IKKalpha functions as a suppressor of lung ADC in human and mice through a unique mechanism that regulates tumor cell-associated ROS metabolism. |
