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

Molecular Cancer

Research

Payel Chatterjee¹  Stefan Duensing²  Anette Duensing³  Nina Korzeniewski⁴  Sarah Wheeler⁵ 

[1] Cancer Virology Program, University of Pittsburgh Cancer Institute, 15213, Pittsburgh, PA, USA;Cancer Virology Program, University of Pittsburgh Cancer Institute, 15213, Pittsburgh, PA, USA;Department of Microbiology and Molecular Genetics, University of Pittsburgh School of Medicine, 15219, Pittsburgh, PA, USA;Cancer Virology Program, University of Pittsburgh Cancer Institute, 15213, Pittsburgh, PA, USA;Department of Pathology, University of Pittsburgh School of Medicine, 15261, Pittsburgh, PA, USA;Cancer Virology Program, University of Pittsburgh Cancer Institute, 15213, Pittsburgh, PA, USA;Molecular Virology and Microbiology Graduate Program, University of Pittsburgh School of Medicine, 15261, Pittsburgh, PA, USA;Cellular and Molecular Pathology Graduate Program, University of Pittsburgh School of Medicine, 15261, Pittsburgh, PA, USA;

关键词: Aryl Hydrocarbon Receptor;    Indirubin;    Centrosome Amplification;    Aryl Hydrocarbon Receptor Agonist;    Aryl Hydrocarbon Receptor Expression;   

DOI  :  10.1186/1476-4598-9-153

 received in 2009-11-09, accepted in 2010-06-17,  发布年份 2010

来源: Springer

【 摘 要 】

BackgroundCentrosome 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.ResultsAs 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.ConclusionsOur 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.

【 授权许可】

Unknown   
© Korzeniewski et al; licensee BioMed Central Ltd. 2010. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.