1. ¹Breast Cancer Translational Research Laboratory, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
2. ²Department of Blood and Marrow Transplantation, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA
3. ³Graduate School of Biomedical Sciences, The University of Texas Health Science Center, Houston, TX, USA
4. ⁴Department of Tumor Genetics and Biology, Kumamoto University School of Medicine, Kumamoto, Japan
5. ⁵Department of Medicine, University of California–San Diego, La Jolla, CA, USA
6. ⁶Department of Molecular and Cellular Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

Correspondence: Dr NT Ueno, Department of Blood and Marrow Transplantation, Unit 448, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA. E-mail: nueno@mdanderson.org

Received 10 March 2005; Revised 8 July 2005; Accepted 12 July 2005; Published online 19 September 2005.

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.