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The prolyl isomerase Pin1 regulates the NF-κB signaling pathway and interleukin-8 expression in glioblastoma

Oncogene volume 28, pages 3735–3745 (2009)Cite this article

Abstract

The brain tumor glioblastoma (GBM) remains one of the most aggressive and devastating tumors despite decades of effort to find more effective treatments. A hallmark of GBM is the constitutive activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) signaling pathway, which regulates cell proliferation, inflammation, migration and apoptosis. The prolyl isomerase, Pin1, has been found to bind directly to the NF-κB protein, p65, and cause increases in NF-κB promoter activity in a breast cancer model. We now present evidence that this interaction occurs in GBM and that it has important consequences on NF-κB signaling. We demonstrate that Pin1 levels are enhanced in primary GBM tissues compared with controls, and that this difference in Pin1 expression affects the migratory capacity of GBM-derived cells. Pin1 knockdown decreases the amount of activated, phosphorylated p65 in the nucleus, resulting in inhibition of the transcriptional program of the IL-8 gene. Through the use of microarray, we also observed changes in the expression levels of other NF-κB regulated genes due to Pin1 knockdown. Taken together, these data suggest that Pin1 is an important regulator of NF-κB in GBM, and support the notion of using Pin1 as a therapeutic target in the future.

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Acknowledgements

We thank Dr Michael Crowley in the UAB Comprehensive Cancer Center Gene Expression Shared Facility for his assistance with microarray processing, and Dr Cheryl Ann Palmer (University of Alabama at Birmingham) for providing the brain tumor resections. We also thank Dr Yancey Gillespie, UAB Brain Tumor Tissue Core, for glioma and control tissue samples, and express our appreciation to the laboratory of Dr Dale Benos for assistance with the scratch assay. Finally, many thanks to Dr Rafal Bartoszewski for assistance with the qPCR and to Dr Gerald Fuller for reading the paper. This work was supported in part by National Institutes of Health grants CA-97247 (ENB), NS-54158 (ENB and SEN) and IRG-60-001-47 from the American Cancer Society and CA-13148-31 from the NCI (SEN). GPA was supported by the UAB Medical Scientist Training Program, and is currently supported by NIH T32-AI0705.

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Authors and Affiliations

  1. Department of Cell Biology, University of Alabama at Birmingham, Birmingham, AL, USA

    G P Atkinson, S E Nozell, M S Stonecypher & E N Benveniste

  2. Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA

    D K Harrison

  3. Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA

    D Chen

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  1. G P Atkinson
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Correspondence to E N Benveniste.

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Atkinson, G., Nozell, S., Harrison, D. et al. The prolyl isomerase Pin1 regulates the NF-κB signaling pathway and interleukin-8 expression in glioblastoma. Oncogene 28, 3735–3745 (2009). https://doi.org/10.1038/onc.2009.232

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