Abstract

Role of IKKalpha in skin tumorigenesis. The inflammatory microenvironment promotes skin tumorigenesis. However, the mechanisms of how cells protect themselves from inflammatory signals have yet to be revealed. Downregulation of IKKalpha promotes skin tumor progression from papillomas to squamous cell carcinomas, which is frequently accompanied by genomic instability, including aneuploid chromosomes and extra centrosomes. In this study, we found that IKKalpha promoted oligomerization of nucleophosmin (NPM), a negative centrosome duplication regulator, which further enhanced NPM and centrosome association, inhibited centrosome amplification, and maintained genome integrity. Levels of NPM hexamers and IKKalpha were conversely associated with skin tumor progression. Importantly, pro-inflammatory cytokine-induced IKKalpha activation promoted the formation of NPM oligomers and reduced centrosome numbers in mouse and human cells, whereas kinase-dead IKKalpha blocked this connection. Therefore, our findings suggest a previously unknown mechanism in which an IKKalpha-NPM axis may use the inflammatory signal to suppress centrosome amplification, promote genomic integrity, and prevent tumor progression.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011212-06
Application #
8938015
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
2014
Total Cost
Indirect Cost

  Institution

Name
Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code

  Publications

Gray, Zane; Shi, Gongping; Wang, Xin et al. (2018) Macrophage inducible nitric oxide synthase promotes the initiation of lung squamous cell carcinoma by maintaining circulated inflammation. Cell Death Dis 9:642
Song, Na-Young; Zhu, Feng; Wang, Zining et al. (2018) IKK? inactivation promotes Kras-initiated lung adenocarcinoma development through disrupting major redox regulatory pathways. Proc Natl Acad Sci U S A 115:E812-E821
Wang, Xin; Gray, Zane; Willette-Brown, Jami et al. (2018) Macrophage inducible nitric oxide synthase circulates inflammation and promotes lung carcinogenesis. Cell Death Discov 4:46
Zhu, Feng; Willette-Brown, Jami; Song, Na-Young et al. (2017) Autoreactive T Cells and Chronic Fungal Infection Drive Esophageal Carcinogenesis. Cell Host Microbe 21:478-493.e7
Marien, Eyra; Meister, Michael; Muley, Thomas et al. (2016) Phospholipid profiling identifies acyl chain elongation as a ubiquitous trait and potential target for the treatment of lung squamous cell carcinoma. Oncotarget 7:12582-97
Lane, Jamie; Yumoto, Kenji; Azhar, Mohamad et al. (2015) Tak1, Smad4 and Trim33 redundantly mediate TGF-?3 signaling during palate development. Dev Biol 398:231-41
Blackburn, J; Kawasaki, K; Porntaveetus, T et al. (2015) Excess NF-?B induces ectopic odontogenesis in embryonic incisor epithelium. J Dent Res 94:121-8
Xiao, Zuoxiang; Jiang, Qun; Willette-Brown, Jami et al. (2013) The pivotal role of IKK? in the development of spontaneous lung squamous cell carcinomas. Cancer Cell 23:527-40
Xia, Xiaojun; Liu, Shuang; Xiao, Zuoxiang et al. (2013) An IKK?-nucleophosmin axis utilizes inflammatory signaling to promote genome integrity. Cell Rep 5:1243-55
Liu, Shuang; Chen, Zhisong; Zhu, Feng et al. (2012) I?B kinase alpha and cancer. J Interferon Cytokine Res 32:152-8

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