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Regulation of estrogenic and nuclear factor κB functions by polyamines and their role in polyamine analog-induced apoptosis of breast cancer cells

Oncogene volume 20, pages 1715–1729 (2001)Cite this article

Abstract

The natural polyamines -putrescine, spermidine, and spermine- are essential for cell growth and differentiation. Polyamines are involved in several gene regulatory functions, although their mechanism(s) of action has not been elucidated. We investigated the role of polyamines in the function of NF-κB and estrogen receptor-α (ERα), two transcription factors implicated in breast cancer cell proliferation and cell survival, using MCF-7 breast cancer cells. We found that spermine facilitated the binding of ERα and NF-κB to estrogen response element (ERE)- and NF-κB response element (NRE), respectively, and enhanced ERα-mediated transcriptional activation in transient transfection experiments. We also found that the association of the co-regulatory protein CBP/p300 with ERα and NF-κB was increased by spermine treatment of MCF-7 cells. Spermine also increased the nuclear translocation of NF-κB compared to the control. In contrast, treatment of MCF-7 cells with polyamine analogs, BE-3-4-3 and BE-3-3-3, resulted in transcriptional inhibition of both ERE- and NRE-driven reporter plasmids. In addition, polyamine analogs inhibited the association of ERα and NF-κB with CBP/p300 and were unable to facilitate nuclear translocation of NF-κB. APO-BRDU assay demonstrated that polyamine analogs induced apoptosis, with a loss of the anti-apoptotic protein Bcl-2. These data show a gene regulatory function of polyamines involving transcriptional activation of ERα and NF-κB, potentially leading to the up-regulation of genes involved in breast cancer cell proliferation. Our results with BE-3-4-3 and BE-3-3-3 suggest that down-regulation of ERα- and NF-κB-regulated genes is a possible mechanism for the action of polyamine analogs in inducing apoptosis of breast cancer cells.

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Acknowledgements

This work was supported by Public Health Service grants CA 42439, CA 73058, CA 80163 (T Thomas and TJ Thomas), DK 53220 (CM Kinge), Outstanding Breast Cancer Research Grant Awards from the NJ State Commission on Cancer Research (T Thomas and TJ Thomas), and a Grant-in-Aid for Scientific Research from the Ministry of Education, Science and Culture, Japan (A Shirahata).

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Authors and Affiliations

  1. Department of Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, 08903, New Jersey, NJ, USA

    Neha Shah, T J Thomas & Joan S Lewis

  2. Department of Environmental & Community Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, 08903, New Jersey, NJ, USA

    Thresia Thomas

  3. Department of Biochemistry, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, 08903, New Jersey, NJ, USA

    Celine Gelinas

  4. The Environmental and Occupational Health Sciences Institute, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, 08903, New Jersey, NJ, USA

    Thresia Thomas

  5. The Cancer Institute of New Jersey, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, 08903, New Jersey, NJ, USA

    T J Thomas & Thresia Thomas

  6. Center for Advanced Biotechnology and Medicine, University of Medicine and Dentistry of New Jersey-Robert Wood Johnson Medical School, New Brunswick, 08903, New Jersey, NJ, USA

    T J Thomas & Celine Gelinas

  7. Nutritional Sciences Graduate Program, Rutgers-The State University of New Jersey, New Brunswick, 08903, New Jersey, NJ, USA

    Neha Shah

  8. Department of Biochemistry and Molecular Biology, University of Louisville School of Medicine, Louisville, Kentucky, 40292, KY, USA

    Carolyn M Klinge

  9. Faculty of Pharmaceutical Sciences, Josai University, Sakado, 350-02, Saitama, Japan

    Akira Shirahata

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Shah, N., Thomas, T., Lewis, J. et al. Regulation of estrogenic and nuclear factor κB functions by polyamines and their role in polyamine analog-induced apoptosis of breast cancer cells. Oncogene 20, 1715–1729 (2001). https://doi.org/10.1038/sj.onc.1204247

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