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  • Original Article
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Antitumor effect of E1A in ovarian cancer by cytoplasmic sequestration of activated ERK by PEA15

Oncogene volume 25, pages 79–90 (2006)Cite this article

Abstract

The adenovirus type 5 gene E1A is known to suppress tumorigenicity by transcriptionally downregulating HER-2/neu (HER2) or by inducing apoptosis. We show here that E1A also suppressed the tumorigenicity of the low-HER2-expressing ovarian cancer cell line OVCAR-3 by decreasing cell proliferation. We further found that the mechanism responsible for this reduced proliferation is the presence of PEA15 (phosphoprotein enriched in astrocytes), which is upregulated by E1A in ovarian cancer; PEA15 promotes translocation of ERK from the nucleus to the cytoplasm, leading to inhibition of ERK-dependent transcription and proliferation. Indeed, siRNA-mediated knockdown of PEA15 expression in OVCAR-3 stable E1A transfectants resulted in a nuclear accumulation of the active form of ERK, followed by an increase in Elk-1 activity, DNA synthesis, and anchorage-independent growth. Finally, PEA15 by itself suppressed colony formation in breast and ovarian cancer cell lines, in which E1A is known to have antitumor activity. We conclude that part of the antitumor effect of E1A in ovarian cancer results from cytoplasmic sequestration of the activated form of ERK by PEA15.

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Acknowledgements

We thank Christine Wogan of the Department of Scientific Publications at The University of Texas M. D. Anderson Cancer Center for her expert editorial assistance, Bill Spohn for his assistance with the Zeiss microscope and Wendy Schober of the Flow Cytometry and Cellular Imaging Core Facility at The University of Texas M. D. Anderson Cancer Center. We thank Rita Nahta and Geoffrey Bartholomeusz for critically reading the manuscript. This work was supported in part by National Institutes of Health grants CA76450-1 (to NTU) and CA16672-27 (Cancer Center Support Grant), the Nellie B Connally Breast Cancer Research Fund (to the Breast Cancer Translational Research Laboratory), the National Science Foundation/Ministry of Education, Culture, Sports, Science and Technology of Japan Research Experience Fellowship 2002 (to CB) Blanton-Davis Ovarian Cancer Research Award (to CB and NTU) and CA016672-29 (to the Flow Cytometry and Cellular Imaging Core Facility at The University of Texas M. D. Anderson Cancer Center). This work was in partial fulfillment of the requirements for the PhD degree from The University of Texas Graduate School of Biomedical Sciences at Houston (CB).

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Authors and Affiliations

  1. Breast Cancer Translational Research Laboratory, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    C Bartholomeusz, H Itamochi & N T Ueno

  2. Department of Blood and Marrow Transplantation, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    C Bartholomeusz, H Itamochi & N T Ueno

  3. Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, TX, USA

    C Bartholomeusz

  4. Department of Tumor Genetics and Biology, Kumamoto University School of Medicine, Kumamoto, Japan

    M Nitta & H Saya

  5. Department of Medicine, University of California–San Diego, La Jolla, CA, USA

    M H Ginsberg

  6. Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

    N T Ueno

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  1. C Bartholomeusz
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Correspondence to N T Ueno.

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Bartholomeusz, C., Itamochi, H., Nitta, M. et al. Antitumor effect of E1A in ovarian cancer by cytoplasmic sequestration of activated ERK by PEA15. Oncogene 25, 79–90 (2006). https://doi.org/10.1038/sj.onc.1209014

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