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Cyclooxygenase inhibitors modulate the p53/HDM2 pathway and enhance chemotherapy-induced apoptosis in neuroblastoma

Oncogene volume 26, pages 1920–1931 (2007)Cite this article

Abstract

Cyclooxygenase–2 (COX-2) is upregulated in many tumors including neuroblastoma, and its overexpression has been implicated in resistance to p53-dependent apoptosis. Although p53 is rarely mutated in neuroblastoma, the p53 protein is rendered inactive via several mechanisms including sequestration in the cytoplasm. Here, we show that COX inhibitors inhibit the growth of neuroblastoma and when combined with low doses of chemotherapy, exert synergistic effects on neuroblastoma cells. Following COX inhibitor treatment, HDM2, which targets p53 for ubiquitin-mediated degradation, is downregulated, resulting in an attenuation of p53 ubiquitination and an increase in p53 half-life. The level of HDM2 phosphorylation at ser166, which influences both HDM2 and p53 subcellular distribution, is markedly diminished in response to COX inhibitors and is associated with increased p53 nuclear localization. Combining COX inhibitors with low-dose chemotherapy potentiates apoptosis and p53 stability, nuclear localization, and activity. p53 knockdown by siRNA resulted in the rescue of COX-inhibitor-treated cells, indicating that COX inhibitor-induced apoptosis is, at least in part, p53-dependent. Taken together, these results provide the first evidence that COX inhibitors enhance chemosensitivity in neuroblastoma via downregulating HDM2 and augmenting p53 stability and nuclear accumulation.

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Acknowledgements

We thank members of the Irwin Lab for helpful comments and technical suggestions. We thank Drs Michael Ohh, David Malkin, and Annie Huang for critical review of the manuscript, Jennifer Nugent for technical assistance, and members of the lab of Drs David Kaplan and Freda Miller for assistance with primary cell cultures. This project is supported by The James Fund for Neuroblastoma Research at SickKids and the National Cancer Institute of Canada through funding from the Terry Fox Foundation. LL is supported in part by Restracomp (Research Institute, Hospital for Sick Children). DRK is a Canada Research Chair in Cancer and Neuroscience. MSI is Canada Research Chair in Cancer Biology.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Hospital for Sick Children, Toronto, Canada

    L Lau, S Baruchel & M S Irwin

  2. Cancer Research Program, Research Institute, Hospital for Sick Children, Toronto, Canada

    L Lau, L M Hansford, L S Cheng, M Hang, S Baruchel, D R Kaplan & M S Irwin

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  1. L Lau
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  2. L M Hansford
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  3. L S Cheng
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  4. M Hang
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  5. S Baruchel
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Correspondence to M S Irwin.

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc).

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Lau, L., Hansford, L., Cheng, L. et al. Cyclooxygenase inhibitors modulate the p53/HDM2 pathway and enhance chemotherapy-induced apoptosis in neuroblastoma. Oncogene 26, 1920–1931 (2007). https://doi.org/10.1038/sj.onc.1209981

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