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Inhibition of p53 expression by peptide-conjugated phosphorodiamidate morpholino oligomers sensitizes human cancer cells to chemotherapeutic drugs

Oncogene volume 31, pages 1024–1033 (2012)Cite this article

Abstract

The p53 tumor suppressor gene encodes a transcription factor that is commonly mutated in cancer. Tumors arise when premalignant cells are unable to undergo p53-dependent apoptosis, cell cycle arrest or DNA repair. The p53-signaling pathway affects not only tumor development, but also the response of tumors to chemotherapeutic drugs. In this study, we use cell penetrating peptide conjugates of phosphorodiamidate morpholino oligomers (PPMOs) to inhibit p53 expression. We examine the functional properties of endogenous p53 isoforms that are produced upon PPMO-mediated inhibition of p53 translation and splicing, and report that loss of N-terminal or C-terminal sequences interferes with the transcriptional activity of p53. Importantly, we report that PPMO-mediated inhibition of p53 expression sensitizes human cancer cells with wild-type p53 to chemotherapeutic drugs.

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Acknowledgements

This work was supported by a grant from Eleos Inc to SB. SB is supported by a Canada Research Chair.

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Authors and Affiliations

  1. Department of Biology, York University, Toronto, Ontario, Canada

    W Ma, Y Lin, W Xuan & S Benchimol

  2. AVI BioPharma, Inc., Corvallis, OR, USA

    P L Iversen

  3. Eleos Inc., Omaha, NE, USA

    L J Smith

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  1. W Ma
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  2. Y Lin
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  3. W Xuan
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  4. P L Iversen
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  5. L J Smith
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  6. S Benchimol
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Correspondence to S Benchimol.

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Competing interests

SB is a member of the scientific advisory board of Eleos Inc. LJS is the founder and CSO of Eleos Inc. PLI is a full-time employee of AVI Biopharma Inc.

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Supplementary Information accompanies the paper on the Oncogene website

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Ma, W., Lin, Y., Xuan, W. et al. Inhibition of p53 expression by peptide-conjugated phosphorodiamidate morpholino oligomers sensitizes human cancer cells to chemotherapeutic drugs. Oncogene 31, 1024–1033 (2012). https://doi.org/10.1038/onc.2011.300

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