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Cyclooxygenase inhibitors differentially modulate p73 isoforms in neuroblastoma

Abstract

p73 encodes multiple functionally distinct isoforms. Proapoptotic TAp73 isoforms contain a transactivation (TA) domain, and like p53, have tumor suppressor properties and are activated by chemotherapies to induce cell death. In contrast, antiapoptotic ΔNp73 isoforms lack the TA domain and are dominant-negative inhibitors of p53 and TAp73. ΔNp73 proteins are overexpressed in a variety of tumors including neuroblastoma. Thus, identification of drugs that upregulate TAp73 and/or downregulate ΔNp73 represents a potential therapeutic strategy. Here, we report that cyclooxygenase (COX) inhibitors induce apoptosis independent of p53, and differentially modulate endogenous p73 isoforms in neuroblastoma and other tumors. COX inhibitor-mediated apoptosis is associated with the induction of TAp73β and its target genes. COX inhibitors also downregulate the alternative-spliced ΔNp73AS isoforms, Δexon2 and Δexon2/3. Furthermore, forced expression of ΔNp73AS results in diminished apoptosis in response to the selective COX-2 inhibitor celecoxib. Celecoxib-mediated downregulation of ΔNp73AS is associated with decreased E2F1 levels and diminished E2F1 activation of the p73 promoter. These results provide the first evidence that COX inhibitors differentially modulate p73 isoforms leading to enhanced apoptosis, and support the potential use of COX inhibitors as novel regulators of p73 to enhance chemosensitivity in tumors with deregulated E2F1 and in those with wild-type (wt) or mutant p53.

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Acknowledgements

This study was supported by the Canadian Cancer Society and the National Cancer Institute of Canada (CCS Grant no. 019274, MS Irwin), the James Fund for Neuroblastoma Research at SickKids Foundation and Lloyd Carr-Harris Foundation. MS Irwin is a Canada Research Chair in Cancer Biology. L Lau was supported by the Terry Fox Foundation Clinical Research Fellowship (National Cancer Institute of Canada).

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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., Wolter, J., Lau, J. et al. Cyclooxygenase inhibitors differentially modulate p73 isoforms in neuroblastoma. Oncogene 28, 2024–2033 (2009). https://doi.org/10.1038/onc.2009.59

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