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Inhibition of Akt signaling by the lignan matairesinol sensitizes prostate cancer cells to TRAIL-induced apoptosis

Oncogene volume 29, pages 898–908 (2010)Cite this article

Abstract

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has been shown to be selectively pro-apoptotic in cancer cells, with minimal toxicity to normal tissues. Although this feature makes TRAIL a promising anticancer agent, not all cancer cell types are sensitive to TRAIL-induced apoptosis despite abundant expression of TRAIL receptors. Thus, combinatorial treatments to sensitize tumor cells to TRAIL-induced apoptosis have been in the focus of extensive research. Dietary lignans have shown cancer preventive and antitumorigenic activity, but the mechanisms behind these effects are poorly known. Here we observed that of the three tested lignan molecules, matairesinol (MAT) was the most effective as a death receptor-sensitizing agent. MAT sensitized the androgen-dependent LNCaP cells to TRAIL-induced apoptosis both in the presence and absence of androgens. Treatment with MAT markedly decreased Akt activity, which has been implicated as a key signaling mechanism in the TRAIL resistance of LNCaP prostate cancer cells. The involvement of the pathway in the MAT-mediated sensitization was shown in rescue experiments using ectopic expression of constitutively active Akt. Owing to the high activity of phosphatidylinositol 3-kinase/Akt signaling in cancer, targeting this survival pathway with MAT could markedly benefit TRAIL-based tumor therapies, including those aimed at prostate cancer.

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Acknowledgements

We thank Henning Walczak for providing the recombinant izTRAIL, Julian Downward for the ca-Akt construct and Perttu Terho for technical assistance in flow cytometry. We also thank Cecilia Sahlgren and all the members of our laboratory for critical comments on the paper and technical help during the course of this study. This work was supported by the Academy of Finland, the Sigrid Jusélius Foundation, the Research Institute of the Åbo Akademi University, the Foundation of the Åbo Akademi University, K Albin Johansson Foundation, Liv och Hälsa Foundation and Magnus Ehrnrooth Foundation.

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  1. A Rivero-Müller and H Stykki: These authors contributed equally to this work.

Authors and Affiliations

  1. Turku Centre for Biotechnology, University of Turku and Åbo Akademi University, Biocity, Turku, Finland

    E Peuhu, A Rivero-Müller, H Stykki, E Torvaldson & J E Eriksson

  2. Department of Biology, Åbo Akademi University, Tykistökatu, Turku, Finland

    E Peuhu, H Stykki, E Torvaldson & J E Eriksson

  3. Institute of BioMedicine, University of Turku, Kiinamyllynkatu, Turku, Finland

    A Rivero-Müller

  4. Laboratory of Fiber and Cellulose Technology, Åbo Akademi University, Porthansgatan 3, Turku/Åbo, Finland

    T Holmbom

  5. Laboratory of Organic Chemistry, Åbo Akademi University, Biskopsgatan 8, Turku/Åbo, Finland

    P Eklund & R Sjöholm

  6. Hormos Medical Ltd, Itäinen Pitkäkatu 4b, Turku, Finland

    M Unkila

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Supplementary Information accompanies the paper on the Oncogene website (http://www.nature.com/onc)

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Peuhu, E., Rivero-Müller, A., Stykki, H. et al. Inhibition of Akt signaling by the lignan matairesinol sensitizes prostate cancer cells to TRAIL-induced apoptosis. Oncogene 29, 898–908 (2010). https://doi.org/10.1038/onc.2009.386

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