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Inhibition of Egr-1 expression reverses transformation of prostate cancer cells in vitro and in vivo

Oncogene volume 22, pages 4194–4204 (2003)Cite this article

Abstract

Transcription factor early growth response-1 (Egr-1) is a crucial regulator of cell growth, differentiation and survival. Several observations suggest that Egr-1 is growth promoting in prostate cancer cells and that blocking its function may impede cancer progression. To test this hypothesis, we developed phosphorothioate antisense oligonucleotides that efficiently inhibit Egr-1 expression without altering the expression of other family members Egr-2, Egr-3 and Egr-4. In TRAMP mouse-derived prostate cancer cell lines, our optimal antisense oligonucleotide decreased the expression of the Egr-1 target gene transforming growth factor-β1 whereas a control oligonucleotide had no effect, indicating that the antisense blocked Egr-1 function as a transcription factor. The antisense oligonucleotide deregulated cell cycle progression and decreased proliferation of the three TRAMP cell lines by an average of 54±3%. Both colony formation and growth in soft agar were inhibited by the antisense oligonucleotide. When TRAMP mice were treated systemically for 10 weeks, the incidence of palpable tumors at 32 weeks of age in untreated mice or mice injected with the control scramble oligonucleotide was 87%, whereas incidence of tumors in antisense-Egr-1-treated mice was significantly reduced to 37% (P=0.026). Thus, Egr-1 plays a functional role in the transformed phenotype and may represent a valid target for prostate cancer therapy.

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Abbreviations

Egr-1:

early growth response-1

TGF:

transforming growth factor

NAB:

nerve growth factor-I A binding protein

PTEN:

phosphatase and TENsin homolog deleted on chromosome 10

GAPDH:

glyceraldehyde-3-phosphate dehydrogenase

SDS:

sodium dodecyl sulfate

RT–PCR:

reverse transcription–polymerase chain reaction

TPA:

12-O-tetradecanoylphorbol-13-acetate

s.e.:

standard error

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Acknowledgements

We are grateful to Norman Greenberg (Baylor College of Medicine, Houston, Texas, USA) for the generous gift of a breeding pair of TRAMP mice. We also thank Norman Greenberg and Joseph Lustgarten (Sidney Kimmel Cancer Center, San Diego, CA, USA) for kindly providing the TRAMP-C cell lines. This work was supported by the US Public Health Service (grants CA 76173 and CA 84107). We thank the Philippe Foundation (TV and VB) and the Deutscher Akademischer Austauschdienst (AK-H) for their support.

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Author notes

  1. Véronique Baron and Giorgia De Gregorio: These two authors contributed equally to the work

Authors and Affiliations

  1. Sidney Kimmel Cancer Center, 10835 Altman Row, San Diego, 92121, CA, USA

    Véronique Baron, Anja Krones-Herzig, Rafael Urcis & Dan Mercola

  2. Instituto di Ricovero e Cura a Carattere Scientifico, Neuromed, Pozzilli, 86077, Italy

    Giorgia De Gregorio & Antonella Calogero

  3. The Burnham Institute, La Jolla Cancer Research Center, 10901 North Torrey Pines Road, La Jolla, CA, USA

    Thierry Virolle

  4. Cancer Center, University of California San Diego, La Jolla, 92093, CA, USA

    Dan Mercola

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  1. Véronique Baron
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Correspondence to Véronique Baron or Dan Mercola.

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Baron, V., De Gregorio, G., Krones-Herzig, A. et al. Inhibition of Egr-1 expression reverses transformation of prostate cancer cells in vitro and in vivo. Oncogene 22, 4194–4204 (2003). https://doi.org/10.1038/sj.onc.1206560

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