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Tissue inhibitor of metalloproteinases-3 induces apoptosis in melanoma cells by stabilization of death receptors

Oncogene volume 22, pages 2121–2134 (2003)Cite this article

Abstract

Tissue inhibitors of metalloproteinases (TIMPs) are important regulators of matrix metalloproteinase (MMP) and adamalysin (ADAM) activity. We have previously shown that adenovirally expressed tissue inhibitor of metalloproteinases-3 (TIMP-3) induces apoptosis in melanoma cells and inhibits growth of human melanoma xenografts. Here, we have studied the role of death receptors in apoptosis of melanoma cells induced by TIMP-3. Our results show, that the exposure of three metastatic melanoma cell lines (A2058, SK-Mel-5, and WM-266-4) to recombinant TIMP-3, N-terminal MMP inhibitory domain of TIMP-3, as well as to adenovirally expressed TIMP-3 results in stabilization of tumor necrosis factor receptor-1 (TNF-RI), FAS, and TNF-related apoptosis inducing ligand receptor-1 (TRAIL-RI) on melanoma cell surface and sensitizes these cells to apoptosis induced by TNF-α, anti-Fas-antibody and TRAIL. Stabilization of death receptors by TIMP-3 results in activation of caspase-8 and caspase-3, and subsequent apoptosis is blocked by specific caspase-8 inhibitor (Z-IETD-FMK) and by pan-caspase inhibitor (Z-DEVD-FMK). Adenovirus-mediated expression of TIMP-3 in human melanoma xenografts in vivo resulted in increased immunostaining for TNF-RI, FAS, and cleaved caspase-3, and in apoptosis of melanoma cells. Taken together, these results show that TIMP-3 promotes apoptosis in melanoma cells through stabilization of three distinct death receptors and activation of their apoptotic signaling cascade through caspase-8.

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Acknowledgements

We thank Ms Hanna Haavisto, Ms Marjo Hakkarainen, and Ms Sari Pitkänen for their skillful technical assistance. This study was supported by grants from the Academy of Finland, Sigrid Jusélius Foundation, the Cancer Foundation of Finland, and Turku University Central Hospital, and by research contract with Finnish Life and Pension Insurance Companies, and the Wellcome Trust Grant 057508 and NIH Grant AR40994 to Hideaki Nagase. Matti Ahonen and Minna Poukkula are students in Turku Graduate School of Biomedical Sciences.

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Authors and Affiliations

  1. Centre for Biotechnology, University of Turku and Åbo Akademi University, Turku, FIN-20520, Finland

    Matti Ahonen, Minna Poukkula, John E Eriksson & Veli-Matti Kähäri

  2. Department of Medical Biochemistry and Department of Dermatology, University of Turku, Turku, FIN-20520, Finland

    Matti Ahonen & Veli-Matti Kähäri

  3. Department of Biology, University of Turku, Turku, FIN-20014, Finland

    Minna Poukkula & John E Eriksson

  4. Department of Medicine and Therapeutics, University of Glasgow, Glasgow, G11 6NT, UK

    Andrew H Baker

  5. Kennedy Institute of Rheumatology Division, Faculty of Medicine, Imperial College, London, W6 8LH, UK

    Masahide Kashiwagi & Hideaki Nagase

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  1. Matti Ahonen
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Correspondence to Veli-Matti Kähäri.

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Ahonen, M., Poukkula, M., Baker, A. et al. Tissue inhibitor of metalloproteinases-3 induces apoptosis in melanoma cells by stabilization of death receptors. Oncogene 22, 2121–2134 (2003). https://doi.org/10.1038/sj.onc.1206292

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