Link to the University of Pittsburgh Homepage
Link to the University Library System Homepage Link to the Contact Us Form

A novel role of the aryl hydrocarbon receptor (AhR) in centrosome amplification - implications for chemoprevention

Korzeniewski, N and Wheeler, S and Chatterjee, P and Duensing, A and Duensing, S (2010) A novel role of the aryl hydrocarbon receptor (AhR) in centrosome amplification - implications for chemoprevention. Molecular Cancer, 9.

[img]
Preview
PDF
Published Version
Available under License : See the attached license file.

Download (3MB) | Preview
[img] Plain Text (licence)
Available under License : See the attached license file.

Download (1kB)

Abstract

Background: Centrosome aberrations can cause genomic instability and correlate with malignant progression in common human malignancies such as breast and prostate cancer. Deregulation of cyclin/cyclin-dependent kinase 2 (CDK2) activity has previously been shown to be critically involved in centrosome overduplication. We therefore test here whether small molecule CDK inhibitors derived from the bis-indole indirubin can be used to suppress centrosome aberrations as a novel approach to chemoprevention of malignant progression.Results: As expected, we found that the CDK inhibitor indirubin-3'-oxime (IO) suppresses centrosome amplification in breast cancer cells. However, we made the unexpected discovery that indirubin-derived compounds that have been chemically modified to be inactive as kinase inhibitors such as 1-methyl-indirubin-3'-oxime (MeIO) still significantly reduced centrosome amplification. All indirubins used in the present study are potent agonists of the aryl hydrocarbon receptor (AhR), which is known for its important role in the cellular metabolism of xenobiotics. To corroborate our results, we first show that the coincidence of nuclear AhR overexpression, reflecting a constitutive activation, and numerical centrosome aberrations correlates significantly with malignancy in mammary tissue specimens. Remarkably, a considerable proportion (72.7%) of benign mammary tissue samples scored also positive for nuclear AhR overexpression. We furthermore provide evidence that continued expression of endogenous AhR is critical to promote centriole overduplication induced by cyclin E and that AhR and cyclin E may function in the same pathway. Overexpression of the AhR in the absence of exogenous ligands was found to rapidly disrupt centriole duplication control. Nonetheless, the AhR agonists IO and MeIO were still found to significantly reduce centriole overduplication stimulated by ectopic AhR expression.Conclusions: Our results indicate that continued expression of endogenous AhR promotes centrosome amplification in breast cancer cells in a pathway that involves cyclin E. AhR agonists such as indirubins inhibit centrosome amplification even when stimulated by ectopic expression of the AhR suggesting that these compounds are potentially useful for the chemoprevention of centrosome-mediated cell division errors and malignant progression in neoplasms in which the AhR is overexpressed. Future studies are warranted to determine whether individuals in which nuclear AhR overexpression is detected in benign mammary tissue are at a higher risk for developing pre-cancerous or cancerous breast lesions. © 2010 Korzeniewski et al; licensee BioMed Central Ltd.


Share

Citation/Export:
Social Networking:
Share |

Details

Item Type: Article
Status: Published
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Korzeniewski, N
Wheeler, Ssam125@pitt.eduSAM125
Chatterjee, P
Duensing, Aaduensin@pitt.eduADUENSIN
Duensing, S
Centers: Other Centers, Institutes, or Units > Pittsburgh Cancer Institute
Date: 17 June 2010
Date Type: Publication
Journal or Publication Title: Molecular Cancer
Volume: 9
DOI or Unique Handle: 10.1186/1476-4598-9-153
Schools and Programs: School of Medicine > Cellular and Molecular Pathology
School of Medicine > Microbiology and Molecular Genetics
School of Medicine > Molecular Virology and Microbiology
School of Medicine > Pathology
Refereed: Yes
Date Deposited: 10 Nov 2016 18:29
Last Modified: 04 Feb 2019 15:56
URI: http://d-scholarship.pitt.edu/id/eprint/30268

Metrics

Monthly Views for the past 3 years

Plum Analytics

Altmetric.com


Actions (login required)

View Item View Item