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Loss of p14ARF in tumor cells facilitates replication of the adenovirus mutant dl1520 (ONYX-015)

Nature Medicine volume 6, pages 1128–1133 (2000)Cite this article

Abstract

The adenovirus mutant dl1520 (ONYX-015) does not express the E1B-55K protein that binds and inactivates p53. This virus replicates in tumor cells with mutant p53, but not in normal cells with functional p53. Although intra-tumoral injection of dl1520 shows promising responses in patients with solid tumors, previous in vitro studies have not established a close correlation between p53 status and dl1520 replication. Here we identify loss of p14ARF as a mechanism that allows dl1520 replication in tumor cells retaining wild-type p53. We demonstrate that the re-introduction of p14ARF into tumor cells with wild-type p53 suppresses replication of dl1520 in a p53-dependent manner. Our study supports the therapeutic use of dl1520 in tumors with lesions within the p53 pathway other than mutation of p53.

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Figure 1: Response of p53, p21WAF1/CIP1 and Mdm2 in HCT 116 TP53+/+ cells following adenovirus infection.
Figure 2: The adenovirus E1A protein activates p53 independently of p14ARF in HCT 116 TP53+/+ cells.
Figure 3: p14ARF protein levels in normal cells and A2780 cells.
Figure 4: Effect of p14ARF re-introduction into HCT116 TP53+/+ cells on p53.
Figure 5: p14ARF protects HCT116 TP53+/+ cells from lysis by dl1520 replication.

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Acknowledgements

We thank B. Vogelstein and F. Bunz for the HCT116 cell lines; E. Lees for the p14ARF antibody and the pCMV-p14ARFexpression plasmid; H. Jiang, Y.J. Shen and O. Tetsu for technical advice; J. Giovanola and K. Halfmeyer for technical assistance; D. Moore for helping with the statistical analysis; A. Fattaey, L. Johnson, C. O'Shea and J. Lyons for suggestions and reagents; and B. Bastian for discussions. S.J.R. is a recipient of a fellowship as part of the “Gemeinsames Hochschulsonderprogramm III von Bund und Ländern” granted by the German Academic Exchange Service, DAAD. C.H.B. is the recipient of a fellowship granted by the Deutsche Forschungsgemeinschaft (DFG).

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Authors and Affiliations

  1. Cancer Research Institute, Comprehensive Cancer Center, University of California San Francisco, San Francisco, 94143-0128, California, USA

    Stefan J. Ries, Christian H. Brandts, Alicia S. Chung, Carola H. Biederer, Byron C. Hann, Ettie M. Lipner & Frank McCormick

  2. Division of Gastroenterology, Department of Medicine, University of California San Francisco, San Francisco, 94143-0128, California, USA

    W. Michael Korn

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Ries, S., Brandts, C., Chung, A. et al. Loss of p14ARF in tumor cells facilitates replication of the adenovirus mutant dl1520 (ONYX-015). Nat Med 6, 1128–1133 (2000). https://doi.org/10.1038/80466

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